Endoplasmic reticulum stress in disease pathogenesis: its implications for therapy.

ER stress is increasingly recognized as a critical player in the pathophysiology of various diseases. Emerging evidence links ER stress to a wide array of conditions, including cancers, cardiovascular disorders, neurodegenerative diseases, metabolic diseases, and autoimmune diseases. Understanding the multifaceted roles of ER stress in these diseases may provide insights into novel treatment strategies, underscoring the importance of this cellular stress response in both health and disease. Tumorigenesis is a progressive process that involves a multistage response and the accumulation of mutations. 193 As this process progresses, cancer cells increasingly evade in vivo regulatory mechanisms, leading to the invasion of normal tissues and endowing mutant cells with new characteristics, including ER dysfunction. 194 ER stress plays a pivotal role in cancer biology, influencing tumor initiation, progression, and response to therapy. In the context of cancer, the UPR can have dual roles. On the one hand, it promotes cell survival and tumor growth by enhancing metabolic adaptation and resistance to apoptosis. On the other hand, prolonged ER stress can induce cell death, highlighting the delicate balance between survival and apoptosis that cancer cells exploit. Understanding the intricate relationship between ER stress and cancer pathophysiology is crucial for developing innovative therapeutic approaches to improve patient outcomes. We summarize recent studies on lung cancer, breast cancer, colorectal cancer, prostate cancer, gastric cancer, hepatocellular carcinoma, glioblastoma, melanoma, ovarian cancer, and leukemia, including studies on the role of ER stress in tumors and immune cells in cancer (Table 1 ). Table 1 Effects of ER stress in solid tumors Cancer type Key ER stress pathways Key molecules/regulators Impact on the tumor Therapeutic targets/strategies Lung cancer IRE1/XBP1, PERK/ATF4, GRP78 GRP78, SLC7A11, CYB5R3, CHOP - GRP78 is linked to better prognosis. Targeting CYB5R3, SLC7A11 inhibition, and CHOP modulation. - CYB5R3 induces apoptosis via PERK/ATF4 and IRE1/JNK. - CHOP in MDSCs impairs T-cell responses. Gastric cancer PERK/ATF4, IRE1/XBP1, GRP78 SEC23A, SCNN1B, HAND1 - SEC23A promotes autophagy to evade apoptosis. Targeting SEC23A, SCNN1B activation, HAND1 overexpression. - SCNN1B triggers caspase-dependent apoptosis. - HAND1 induces ER stress via ROS. Colorectal cancer IRE1/XBP1, PERK/eIF2α, ATF4 XBP1, KLF16, DEH, GCS1 - XBP1 in TAMs promotes pro-tumor cytokines. XBP1 inhibition, DEH as a therapeutic agent, and KLF16 targeting. - DEH induces autophagy via PERK/IRE1. - GCS1 reduces ER stress-mediated apoptosis. Hepatocellular carcinoma IRE1/XBP1, ATF6, PERK/ATF4 SEC63, GPR109A, FGF19 - IRE1-phosphorylated SEC63 promotes metastasis. SEC63 inhibition, GPR109A blockade, ATF4 suppression (e.g., DSF/Cu). - GPR109A blockade enhances CD8 + T-cell response. - FGF19 counteracts ER stress via ATF4. Prostate cancer IRE1/XBP1, ATF6, PERK/ATF4 AR, DRP1, ACSS3, ATF6 - AR induces ER stress genes. ATF6 inhibitors, ACSS3 restoration, EPHB4 inhibition. - ACSS3 restoration increases ER stress-induced apoptosis. - ATF6 deletion inhibits metastasis. Breast cancer IRE1/XBP1, PERK/CHOP, METTL3/14 IRE1, METTL3, METTL14, σ2 receptor - IRE1 knockdown normalizes vasculature. IRE1 inhibitors, METTL3/14 targeting, σ2 receptor agonists (e.g., A011). - METTL3/14 enhance m6A methylation. - σ2 ligands induce PERK/CHOP apoptosis. Ovarian cancer IRE1/XBP1, PERK/ATF4, UPR in TME HOOK1, XBP1, TAGLN2, SCD - XBP1 in DCs disrupts antigen presentation. XBP1 inhibition in DCs, SCD targeting (e.g., lipid metabolism modulators), and Elaiophylin (autophagy inhibitor). - SCD knockdown induces apoptosis via IRE1/PERK. - TAGLN2 enhances CD8 + T-cell cytotoxicity. Glioma IRE1/XBP1, PERK/ATF4, GRP78 GRP78, UBE2D3, FKBP9, TRPV1 - GRP78 knockdown reduces chemoresistance. GRP78 inhibitors (e.g., temozolomide adjuvants), TRPV1 activation via NO release. - FKBP9 deletion activates IRE1/XBP1-induced apoptosis. - TRPV1 activation inhibits invasion. Melanoma IRE1/XBP1, PERK/CHOP TRAIL-R2, RIPK1, B7H6 - ER stress enhances BRAFi-induced apoptosis. RIPK1 inhibitors, PERK pathway blockade, and CO-induced ER stress modulation. - RIPK1 knockdown sensitizes cells to ER stress. - PERK inhibition enhances PD-1 efficacy. Effects of ER stress in solid tumors In 2005, Uramoto et al. first studied the expression of GRP78 in human lung cancer and its clinical significance. 195 Lung cancer patients with positive GRP78 expression tended to have a better prognosis; therefore, the ER stress pathway mediated by GRP78 might be responsible for controlling the growth of lung cancer cells. Oncogenic KRAS is a major driver of lung cancer, and Hu’s team probed the mechanism involved in ER stress. 196 Inhibiting solute carrier family 7 member 11 (SLC7A11) increases the activation of IRE1, PERK, and GRP78 as well as the transcription of CHOP, ATF4, and ATF6. Intense oxidative stress and ER stress-mediated apoptosis are cytotoxic to KRAS-mutant tumors. Furthermore, Xu et al. reported that O-GlcNAc transferase (OGT) significantly enhances the growth, migration, and invasion of lung cancer cells, and its mechanism is inextricably linked to ER stress. 197 OGT induced palmitate production, which increased the protein expression of GRP78 and IRE1, leading to severe activation of the oncogenic pathways JNK/c-jun/AP1 and NF-κB. A new tumor suppressor, Cytochrome b5 reductase 3 (CYB5R3), which induces ER stress-mediated apoptosis in lung cancer cells through the PERK/ATF4 and IRE1/JNK pathways, was identified in 2024. 198 Metabolomic analysis revealed that the overexpression of CYB5R3 also increased nicotinamide adenine dinucleotide (NAD+) production, a process that activates ER-resident protein poly (ADP-ribose) polymerase 16 (PARP16), which similarly induces ER stress. In 2009, Zhang et al. first reported the effects of ER stress on gastric cancer cells. 199 Inhibition of MEK blocked GRP78 upregulation and enhanced ER stress-induced apoptosis in gastric cancer cells through a caspase-dependent mitochondria-mediated mechanism. Recently, preprotein translocation factor (SEC62) was shown to be significantly upregulated in gastric cancer and to promote the migration and invasion of gastric cancer cells. 200 SEC62 activates autophagy by affecting PERK/ATF4 expression and UPR recovery, which promotes gastric cancer metastasis. In gastric cancer, ER stress promotes autophagy by increasing the transcript level of Sec23 homolog A (SEC23A), which in turn regulates the cellular localization of Annexin A2 (ANXA2). 201 ER stress, SEC23A, and autophagy form a negative feedback loop to maintain the survival advantage of gastric cancer cells from ER stress-induced apoptosis. Owing to the tumor cell protective function of SEC23A under ER stress, it may be a promising therapeutic target that is expected to limit the progression of gastric cancer. Moreover, Kuang et al. reported that ectopic expression of hand-and-neural-crest-derivative-expressed 1 (HAND1) can inhibit the growth and migration of gastric cancer cells. 202 Mechanistically, HAND1 expression increases ROS levels and the cytosolic calcium ion concentration, which further kills tumor cells through ER stress-mediated apoptosis. In 2006, Guichard et al. applied ER stress for the first time in the treatment of colorectal cancer, and they reported that dihydroxyphenylethanol (DEH) induced apoptosis in colorectal cancer cells by promoting both branches of IRE1/XBP1/GRP78 and PERK/eIF2α. 203 For the first time, the anticancer effects of DEH on colorectal cancer and its mechanism were investigated by Li et al. 204 Experiments revealed that DEH induced ER stress by activating the PERK/eIF2α and IRE1/XBP1 pathways, which stimulated autophagy in tumor cells, suggesting that DEH may be a potential anticolorectal cancer drug. In studying the effects of metabolic pathways on colorectal cancer, Lin’s team noted that tumor tissues have higher levels of cysteine, which may result from the upregulation of genes encoding cysteine transporters (SLC1A4, SLC1A5) regulated by ROS and ER stress through the transcription factor ATF4. 205 Recently, Chen et al. investigated a pathway that affects colorectal cancer cell survival and apoptosis decisions and experimentally confirmed that glucosidase I (GCS1) expression is significantly upregulated in colorectal cancer. 206 GCS1 functions to bind GRP78 and promote its degradation, which also leads to reduced ER stress-mediated apoptosis in colorectal cancer cells and promotes colorectal cancer progression. As early as 2003, Shuda’s team revealed the involvement of the ER stress pathway genes ATF6, XBP1, and GRP78 in hepatocellular carcinoma. 207 Recent studies have indicated that SEC63 is a new regulator of metabolism in hepatocellular carcinoma cells. 208 When ER stress occurs, the IRE1 pathway phosphorylates SEC63 at T537, thereby activating SEC63, which functions to promote metastasis in hepatocellular carcinoma cells. Furthermore, the ATF6 pathway often acts in conjunction with IRE1. An early study revealed that in macrophages, oxidized low-density lipoprotein (ox-LDL) causes the upregulation of scavenger receptor cluster of differentiation 36 (CD36), which leads to the upregulation of IRE1 and the induction of the nuclear translocation of ATF6, thereby activating ER stress. 209 In addition, Teng and colleagues reported that FGF19 protects hepatocellular carcinoma cells from ER stress, mainly through the ability of ATF4 to directly bind to the FGF19 promoter and thus counteract the stress response. 210 Recently, He et al. reported that during ER stress-driven hepatocellular carcinoma progression, HMMR derived from CHOP transcription alleviates ER stress by promoting autophagy-lysosomal activity, which could play a role in controlling the progression of hepatocellular carcinoma. 211 In 2004, GRP78 was first revealed to be a functional molecular target for identifying prostate cancer patients for clinical application. 212 Furthermore, in prostate cancer, c-MYC is one of the highly activated oncogenic pathways and is closely related to UPR pathway genes. 38 IRE1/XBP1 pathway activity is required for the c-MYC signaling pathway, which in turn promotes prostate cancer progression. In a subsequent study, acyl-CoA synthetase short-chain family member 3 (ACSS3) was found to be downregulated and was associated with poor prognosis. 213 Zhou et al. reported that restoring ACSS3 expression in prostate cancer cells significantly increased ER stress-induced apoptosis, in which the expression of CHOP, PERK, ATF6, and XBP1 was significantly increased. Pachikov’s team confirmed that ATF6 is a new promising target for prostate cancer therapy. 214 Through ethanol stimulation, S1P and S2P in the Golgi apparatus of prostate cancer cells are translocated to the ER, leading to ATF6 cleavage, thereby activating ER stress. Mouse experiments revealed that ATF6 deletion significantly retarded the growth and metastasis of prostate tumor cells. Among other factors, the phosphorylation of eIF2α, a feature of ICD, promoted cell death in prostate cancer cells, suggesting a potential role for EPHB4 inhibition in immunotherapy. Blomme’s team reported that 2,4-dienoyl-CoA reductase (DECR1) deletion decreases prostate tumor cell growth via a mechanism in which DECR1 disrupts the balance between saturated and unsaturated phospholipids, leading to ER stress. 215 This process increases the sensitivity of prostate tumor cells to iron death, leading to the inhibition of tumor growth. In 2004, the expression of VEGF and IL-8 in human breast cancer was reported to be sensitive to ER stress, which affects mainly the upregulation of GRP78 expression. 216 Metabolic analysis of breast cancer cells revealed that GRP78 expression increased the intracellular linoleic acid concentration, and its inhibition increased macrophage infiltration, thereby reducing breast tumor growth. 217 Harnoss’ team reported that IRE1 knockdown significantly reversed ER stress adaptation in breast cancer cells, which led to normalization of the tumor vasculature and slowed breast cancer progression. 218 Moreover, IRE1 disruption also led to remodeling of the TME, reducing the number of cancer-associated fibroblasts and myeloid-derived suppressor cells. In 2024, Wang’s team reported for the first time that ER stress can significantly increase the level of m6A methylation in breast cancer cells through XBP1-dependent upregulation of METTL3 and METTL14 transcription. 219 This process enhances the stability of ER phagocytosis regulator mRNAs, thereby increasing the degree of phagocytosis, which demonstrates that METTL3 and METTL14 may be potential therapeutic targets for breast cancer. Additionally, activated human epidermal growth factor receptor 2 (HER2) can also be sensitized to apoptosis under ER stress via a PERK/ATF4/CHOP-dependent pathway, which has important therapeutic value against breast tumor cells. 220 In 2006, Lei et al. reported for the first time that the activation of the ER stress response in ovarian cancer cells inhibited the proliferation of ovarian cancer cells by upregulating GRP78 via the use of 1,1-bis(3′-indolyl)-1-(p-t-butylphenyl)methane (DIM-C-pPhtBu). 221 In a recent study, Carnero et al. identified a novel ovarian cancer therapeutic target, HOOK1. 222 As a result, UPR signaling was activated in HOOK1-downregulated tumor cells, causing an increase in ER stress and leading to cancer stem cell death. In a recent study, Zhao’s team used lipidomics and stimulated Raman scattering (SRS) microscopy to confirm that stearoyl CoA desaturase (SCD) knockdown leads to rapid activation of the IRE1/XBP1 and PERK/eIF2α/ATF4 axes in the ER stress response. The XBP1 and PERK/eIF2α/ATF4 axes are involved in the ER stress response, which leads to apoptosis and tumor growth inhibition in ovarian cancer cells. 184 Additionally, Li et al. developed a novel autophagy inhibitor, Elaiophylin, which induces apoptosis in ovarian cancer cells by triggering excessive ER stress through overactivation of the MAPK pathway. 223 The results of gene set enrichment analysis (GSEA) revealed that elaiophylin was able to activate ER stress by increasing the protein levels of ATF4 and CHOP. B cells are the main component of humoral immunity and are the most extensively studied cells in leukemia or lymphoma. In 2010, ER stress was shown to be a novel target for the treatment of chronic lymphocytic leukemia (CLL) by Rosati et al. Downregulation of ER signaling by siRNA with BiP/GRP78 increased apoptosis in CLL cells. 224 Tang et al. established a mouse model of CLL that lacks XBP1 in B cells to explore how ER stress regulation affects disease progression. 35 XBP1 deficiency resulted in significantly slower leukemia progression. In addition, researchers have developed a potent IRE1 RNase inhibitor called B-I09. Since the immune system of CLL patients may be unable to clear abnormal B cells effectively, B-I09 may inhibit disease progression by inducing B-apoptosis. This is likely because ER stress renders XBP1 critical for plasma cell differentiation and immunoglobulin secretion, making it an attractive therapeutic target. 225 In addition, Lamothe’s team investigated the mechanism by which carfilzomib induces CLL cell death, which is inextricably linked to ER stress. 226 Carfilzomib treatment resulted in elevated protein levels of ATF4 and CHOP, while the accumulation of CHOP increased the cytotoxicity to CLL cells, which contributed to increased CLL apoptosis. In 2006, Yanamandra et al. validated for the first time the mechanism of action of tipifarnib and bortezomib in acute myeloid leukemia (AML), where enhanced activation of the ER stress response under conditions of fibronectin adhesion led to apoptosis in AML cells. 227 Touriol’s team studied the mechanism by which ER stress affects chemotherapy sensitivity. 228 Sustained activation of XBP1 expression in AML cells induces apoptosis. In contrast, moderate XBP1 expression enhances chemosensitivity, possibly because the genes downstream of XBP1, miR-22-3p or miR-22, significantly reduce cell viability. Furthermore, a recent study revealed that the XBP1/miR-22/SIRT1 axis plays a critical role in AML, its triggering of ER stress induces apoptosis in AML cells, and moderate XBP1 expression enhances chemosensitivity. 228 In 2009, Hernández-Espinosa’s team combined L-asparaginase (L-ASP) and dexamethasone for the treatment of acute lymphoblastic leukemia (ALL), which promoted the expression of GRP78, leading to an exacerbation of the UPR, and the use of this regimen reduced the risk of thrombosis. 229 Both animal and clinical trials have demonstrated that high expression levels of the UPR downstream effector XBP1 predict poor B-ALL prognosis. 230 In a recent study, the development of T-ALL induced strong activation of PERK in the myeloid endothelial vascular ecological niche, which in turn led to increased angiogenesis via PERK/eIF2a/ATF4 axis activation. 231 Liu et al. reported that specific deletion of PERK improved the number of bone marrow endothelial cells, promoted ALL apoptosis, and increased overall survival. In 2007, Pyrko et al. first identified the UPR regulator BiP/GRP78 as a new target for the treatment of glioma, and knocking down BiP/GRP78 reduced the resistance of tumor cells to temozolomide. 232 Obacz’s team reported that this may be because the IRE1/XBP1 pathway increases the expression of the ubiquitin-binding E2 enzyme (UBE2D3), which activates the NF-κB pathway and leads to bone marrow infiltration in glioma. 233 Recently, the downregulation of FK506-binding protein 9 (FKBP9) was shown to significantly inhibit the growth of glioma cells. 234 Deletion of FKBP9 activated the IRE1/XBP1 pathway, which enhanced the apoptotic process of tumor cells via ER stress. Li’s team also recently discovered an important indicator related to the development of glioma. SelK-induced downregulation of ER stress led to the upregulation of β-TrCP1 expression, which accelerated ubiquitin-dependent CDK4 degradation and ultimately impaired glioma cell growth. 235 A recent study revealed that the transient receptor potential vanilloid 1 (TRPV1) ion channel is overexpressed on the ER in glioma cells and that its activation can regulate ER stress and thus inhibit the invasion of glioma. 236 Li et al. successfully activated the TRPV1 ion channel via in situ release of nitric oxide (NO), leading to multimodal killing of tumor cells, which is an effective strategy to inhibit glioma. In 2007, Jiang et al. first used the ER stress inducer tunicamycin for the treatment of melanoma, which can sensitize melanoma cells to apoptosis by activating IRE1 and ATF6 and thus upregulating TRAIL-R2. 237 When melanoma cells are subjected to pharmacological ER stress induced by tunicamycin (TM) or thapsigargin (TG), IRE1/XBP1 is activated and thus enhances heat shock factor protein 1 (HSF1) expression, leading to increased receptor (TNFRSF)-interacting protein kinase 1 (RIPK1) expression in melanoma cells. 238 RIPK1 enhances melanoma cell survival through the activation of autophagy, suggesting that the knockdown of RIPK1 may be a useful strategy to increase the sensitivity of melanoma cells to therapeutic agents that induce ER stress. Niessner’s team reported that BRAF inhibitors (BRAFis) induce ER stress, thereby amplifying their proapoptotic activity in melanoma, where BRAFis significantly activate the PERK/ATF4/CHOP pathway and phosphorylate eIF2α. 239 In lung cancer, studies have shown that ER stress is a key hub for tumor immunosuppression by regulating the function and survival of MDSCs. In particular, in tumor-infiltrating MDSCs, UPR activation is followed by elevated levels of CHOP, which is directly related to the ability of MDSCs to impair T-cell responses. 240 MDSCs maintain survival and enhance immunosuppression in the harsh tumor microenvironment through CHOP-dependent stress adaptation mechanisms. Inhibition of CHOP or upstream stress signals (e.g., ROS/PNT scavengers) may reverse the immunosuppressive function of MDSCs and enhance antitumor immunity. 241 CHOP-deficient MDSCs lose their immunosuppressive capacity due to decreased IL-6 secretion and reduced STAT3 activity, instead promoting antitumor T-cell responses and significantly delaying tumor growth. CHOP-deficient MDSCs exhibit reduced apoptosis but impaired function, suggesting that ER stress plays a key role in balancing MDSC survival and function (Fig. 4 ). Fig. 4 Role of ER stress in the tumor-immune microenvironment. The ER stress response plays a key role in the activation and functional maintenance of immune cells. CO-induced activation of PERK in CD8+ T cells improves the antitumor function of CD8+ T cells and enhances mitochondrial function. ROS cause ER stress via the PERK/CHOP pathway, leading mainly to an increased immune response in CD8+ T cells. Cholesterol enrichment in the TME properly activated the ER stress signaling pathway in CD8+ T cells, and XBP1 was significantly upregulated during this process, promoting the apoptosis of tumor cells. Effective inhibition of IRE1/XBP1 induces B-apoptosis to suppress leukemia progression. Excessive activation of the IRE1/XBP1 pathway in DCs impairs their antigen-presenting capacity, leading to diminished antitumor capacity of T cells. Inhibition of XBP1 expression in DCs restored their immune properties and enhanced the immunocompetence of CD8+ T cells. Excessive activation of the IRE1 and ATF6 signaling pathways in NK cells reduces their cytotoxicity. When either of these two major regulators is knocked down, cytotoxicity to tumor cells can be activated. Excessive IRE1 also directly regulates the c-MYC signaling pathway and mitochondrial respiration to inhibit NK cell proliferation. In addition, ER stress promotes the expression of the NK cell ligand B7H6 through proper activation of eIF2α phosphorylation via PERK signaling, thereby controlling tumor progression. In tumor-infiltrating MDSCs, excessive UPR activation is followed by elevated CHOP levels, which can promote MDSC apoptosis, leading to reduced tumor cell survival time. Excessive activation of either IRE1/XBP1 or GRP78 in TAMs inhibits macrophage phagocytosis, which drives cancer progression, whereas weakening of XBP1 enhances phagocytosis by tumor cells Role of ER stress in the tumor-immune microenvironment. The ER stress response plays a key role in the activation and functional maintenance of immune cells. CO-induced activation of PERK in CD8+ T cells improves the antitumor function of CD8+ T cells and enhances mitochondrial function. ROS cause ER stress via the PERK/CHOP pathway, leading mainly to an increased immune response in CD8+ T cells. Cholesterol enrichment in the TME properly activated the ER stress signaling pathway in CD8+ T cells, and XBP1 was significantly upregulated during this process, promoting the apoptosis of tumor cells. Effective inhibition of IRE1/XBP1 induces B-apoptosis to suppress leukemia progression. Excessive activation of the IRE1/XBP1 pathway in DCs impairs their antigen-presenting capacity, leading to diminished antitumor capacity of T cells. Inhibition of XBP1 expression in DCs restored their immune properties and enhanced the immunocompetence of CD8+ T cells. Excessive activation of the IRE1 and ATF6 signaling pathways in NK cells reduces their cytotoxicity. When either of these two major regulators is knocked down, cytotoxicity to tumor cells can be activated. Excessive IRE1 also directly regulates the c-MYC signaling pathway and mitochondrial respiration to inhibit NK cell proliferation. In addition, ER stress promotes the expression of the NK cell ligand B7H6 through proper activation of eIF2α phosphorylation via PERK signaling, thereby controlling tumor progression. In tumor-infiltrating MDSCs, excessive UPR activation is followed by elevated CHOP levels, which can promote MDSC apoptosis, leading to reduced tumor cell survival time. Excessive activation of either IRE1/XBP1 or GRP78 in TAMs inhibits macrophage phagocytosis, which drives cancer progression, whereas weakening of XBP1 enhances phagocytosis by tumor cells RNA sequencing and immunofluorescence analysis revealed that the spliced form of XBP1 was significantly upregulated and positively correlated with the expression of ER stress markers (e.g., BIP and CHOP) in tumor-associated macrophages (TAMs) from colorectal cancer patients and mouse models. 242 This activation was not observed in normal tissue macrophages, suggesting that the tumor microenvironment is an important trigger for XBP1 activation. XBP1 directly binds and regulates the transcription of protumorigenic cytokines (e.g., IL-6, VEGFA, and IL-4). Knockdown of XBP1 significantly reduced the expression of these cytokines, thereby inhibiting tumor cell proliferation and metastasis. In addition, experiments revealed that the knockdown of XBP1 also reduced the expression of SIRPα and THBS1, which could significantly enhance the phagocytosis of TAMs and disrupt the immune escape of tumor cells. Analysis of clinical data revealed that TAMs with high XBP1 expression were closely associated with poorer survival in colorectal cancer patients. Therefore, targeting XBP1 signaling in TAMs may be a potential strategy for colorectal cancer therapy. A study by Márquez et al. revealed that stimulation of dendritic cells (DCs) by pathogen-associated molecular patterns activates not only IRE1 signaling but also, to a lesser extent, the PERK signaling pathway. 243 In addition, ER stress induces DCs to produce IL-23, which has been proven to be a major driver of colorectal cancer cell growth. 244 Inhibition of IRE1α nucleic acid endonuclease activity or PERK reduces IL-23 production and may be a new direction for the treatment of colorectal cancer or other IL-23-dependent inflammatory diseases. To improve the immunotherapeutic efficacy against hepatocellular carcinoma, Yang and her team reported that blocking GPR109A in tumors triggers antitumor responses in CD8+ T cells. 245 Myeloid cells compete with tumor cells for glutamine uptake, disrupting myeloid ER homeostasis and promoting GPR109A expression via the IRE1/XBP1 pathway. If the IRE1/XBP1 signaling pathway is inhibited or glutamine is supplemented, the immunosuppressive effect of GPR109A can be eliminated, suggesting that GPR109A may be a potential drug target for treating hepatocellular carcinoma. Furthermore, IRE1 is involved in the cytotoxicity of natural killer (NK) cells together with ATF6. 246 Knocking down IRE1 and ATF6 in hepatocellular carcinoma cells significantly increased their sensitivity to NK cell-mediated killing. During UPR activation, the IRE1 and ATF6 signaling pathways decrease the sensitivity of NK cells to cytotoxicity. This decrease in sensitivity is due to the indirect effects of the ATF6 and IRE1 signaling pathways on the expression of the NK cell receptor CD226. When knocked down, either of these two master regulators can activate cytotoxicity in hepatocellular carcinoma cells. 247 In breast cancer, Wen et al. reported that 6-epi-ophiobolin G (MHO7) can induce immunogenic cell death through the CHOP pathway during ER stress. The upregulation of MHO7 triggers ROS, which leads to ER stress through the PERK/CHOP pathway, leading mainly to an increase in CD8+ T-cell immune responses. 248 Additionally, MHO7 triggers oxidative stress through ROS generation and glutathione depletion, further exacerbating ER stress. This leads to elevated cytoplasmic Ca ion levels, thereby collapsing the mitochondrial membrane potential and promoting apoptosis. 249 Knockdown of CHOP partially reversed MHO7-induced Bax expression and Caspase-3 activation, a process that enhances tumor immunogenicity and induces a strong immune response. In a mouse model, MHO7-pretreated tumor cells induced long-term immune memory, inhibited secondary tumor formation, and significantly prolonged mouse survival. In ovarian cancer, recent discoveries indicate that prolonged activation of the IRE1/XBP1 pathway in some DCs within the TME upregulates various UPR factors and induces lipid accumulation, weakening their antigen-presenting ability. 250 Ovarian tumor-infiltrated DCs exhibit marked upregulation of the expression of UPR factors, including BiP and CHOP, along with potent XBP1 activation. This process, in turn, disrupts the antigen-presenting ability of DCs, thereby weakening the antitumor capacity of T cells. 251 Inhibition of the ER stress response reduces T-cell depletion and improves T-cell antitumor function in the TME. Experiments have shown that tumor-associated DCs lacking XBP1 display significant downregulation of multiple genes involved in triglyceride biosynthesis. The activation of XBP1 leads to aberrant lipid accumulation, which in turn inhibits the ability of tumor-associated DCs to support antitumor T cells, thereby driving ovarian cancer progression. Environmentally induced activation of the IRE1/XBP1 signaling pathway in ovarian cancer limits glutamine abundance, inhibiting CD4+ T-cell mitochondrial respiration. 252 Animal experiments revealed that mice deficient in XBP1 exhibited delayed tumor progression and improved survival. Therefore, controlling targeted IRE1/XBP1 signaling in CD4+ T cells may help to restore the metabolic capacity and antitumor ability of T cells from ovarian cancer patients. In leukemia, IRE1 and XBP1 act as upstream regulators that directly regulate the c-MYC signaling pathway and mitochondrial respiration to control the proliferation of NK cells. The oncogene MYC can activate the UPR of NK cells in multiple ways, affecting ALL cell survival by influencing cell growth, protein synthesis, and cell metabolism. 253 , 254 This landmark study was the first to identify c-MYC as a novel, direct downstream target of XBP1 in the regulation of NK cell proliferation. That same year, it was reported that extracellular vesicles from NK cells could induce ER stress in ALL cells, mediating cell death. 255 NK cell-derived extracellular vesicles activate the UPR by altering the expression of the ER chaperone proteins BiP and Ero1-Lα, ultimately triggering the apoptosis or necrosis of tumor cells. However, these experiments did not identify the key ER stress-related genes involved, highlighting the need for more in-depth mechanistic studies in the future. A recent study by De Leo et al. revealed that in the glioma TME, monocyte-derived macrophages (MDMs) play a key immunosuppressive role through ER stress-mediated metabolic reprogramming, the molecular mechanism of which is closely linked to the PERK signaling pathway. 256 Hypoxia and nutrient deprivation signaling in the glioma microenvironment activate the ER stress sensor PERK, whose downstream transcription factor ATF4 directly upregulates the expression of GLUT1 to increase glucose uptake and glycolysis in MDMs. PERK-driven glucose metabolism not only provides energy for MDMs but also remodels the epigenetic landscape and maintains their immunosuppressive phenotype through lactic acid production and histone lactylation. The inhibition of PERK expression in MDMs prevents histone acetylation, leading to the accumulation of T cells in glioma and the retardation of tumor growth. Knocking down PERK was found to significantly reduce GLUT1 expression and lactate levels, decrease IL-10 secretion, and restore CD8+ T-cell infiltration and function within tumors in MDMs in mouse experiments. Previous melanoma studies have shown that cholesterol enrichment in the TME activates the ER stress signaling pathway in CD8+ T cells. 257 Notably, XBP1, a key ER stress response pathway member, is significantly upregulated during this process. Furthermore, Raines et al. reported that IL-4 increases PERK expression in macrophages within melanoma, promoting the activation of immunosuppressive M2 macrophages. 258 Consequently, inhibition of the PERK pathway in ER stress suppresses the immunosuppressive activity of macrophages and may increase the efficacy of programmed cell death 1 (PD-1) inhibitors. Furthermore, a controlled variable experiment revealed that ER stress promotes the expression of the NK cell ligand B7H6 through the PERK signaling pathway. 259 B7H6 depends on PERK activation of eIF2α phosphorylation to regulate its expression levels and thus control melanoma progression. A recent study revealed that carbon monoxide (CO)-induced ER stress alters mitochondrial function in CD8+ T cells. 260 Specifically, CO-induced transient PERK activation in CD8+ T cells significantly improves their control over melanoma and enhances mitochondrial function. This research offers a novel approach to cancer treatment modalities that target ER stress, highlighting the delicate balance between ER stress sensor activation and the regulation of cellular antitumor capacity. In summary, activation of the PERK signaling pathway in tumor cells impairs the antitumor function of CD4+ T cells. Pharmacological inhibition of PERK in tumor cells can effectively enhance the antitumor function of CD4+ T cells; thus, PERK is a promising immunotherapy target that deserves further study. In cancers, ER stress arises as an adaptive response to intrinsic oncogenic pressures and extrinsic microenvironmental stressors, enabling tumor survival via the UPR. Conversely, chronic ER stress becomes a pathological consequence of accumulated cellular damage, metabolic dysregulation, or therapeutic interventions, triggering apoptosis or immune modulation. Thus, its role is context-dependent and shaped by the interplay between tumor-intrinsic vulnerabilities and external pressures. Moreover, ER stress plays a dual role in cancer biology, acting as a double-edged sword through its regulation of the UPR. While adaptive UPR activation promotes tumor survival by enhancing metabolic reprogramming, stress tolerance, and immune evasion, sustained ER stress triggers proapoptotic signaling via pathways such as PERK/ATF4/CHOP and IRE1/JNK, indicating therapeutic potential. Mechanistically, ER stress intersects with oncogenic drivers, immune modulation, and metabolic adaptations, shaping tumor progression and therapy resistance across diverse cancers. Targeting UPR components or combining UPR inhibitors with immunotherapies holds promise for precision oncology. However, challenges remain in balancing prosurvival and pro-death UPR outputs to avoid off-target effects. Future studies should elucidate the spatiotemporal dynamics of ER stress in the tumor microenvironment and validate novel therapeutic strategies. Cardiovascular diseases are leading causes of morbidity and mortality worldwide, which drive healthcare utilization and severely impact quality of life. 261 These diseases include atherosclerosis, I/R injury, MI, and heart failure (HF). 262 Pathologic factors in cardiovascular diseases, such as metabolic diseases, hypoxia, and inflammation, can increase the burden of protein folding within the ER, thereby triggering ER stress. In cardiomyocytes and vascular cells, ER stress can be activated under various conditions, some of which are associated with the development of pathology. The cause and effect of ER stress in several cardiovascular diseases are described in detail below (Fig. 5 ). Fig. 5 Role and influence of ER stress in four common types of diseases. Genetic and metabolic abnormalities, inflammation, hypoxia, and other factors can induce ER stress and thus lead to disease. Cardiac pressure overload or ischemia triggers ER stress, leading to protein-folding dysfunction in cardiomyocytes and activation of the UPR, which increases metabolic disturbances, hypoxia, and inflammatory responses in the heart. ER stress reflects both adaptive and maladaptive effects in cardiovascular disease. Early activation of pathways such as the ATF6 or IRE1/XBP1 pathway promotes cytoprotection and restores ER homeostasis, whereas sustained PERK/CHOP signaling often leads to pathological remodeling, apoptosis, and clinical deterioration. ER dysfunction not only leads to protein-folding errors but also affects processes such as mitochondrial function, calcium homeostasis, and cellular autophagy, which in turn trigger neurodegeneration. The aggregation of β-amyloid and tau proteins triggers ER stress, leading to neuronal dysfunction and further aggravating cognitive impairment. Chronic ER stress exacerbates neurodegeneration by driving neuroinflammation, synaptic deficits, and apoptosis. In patients with obesity and type 2 diabetes mellitus, ER stress is often responsible for the impairment of pancreatic β-cell function and insulin secretion disorders, which leads to decreased glucose utilization and loss of pancreatic cell function. Activation of the UPR pathway inhibits normal pancreatic β-cell function and promotes an inflammatory response in adipose tissue. ER stress stems from metabolic overload, triggering maladaptive UPR signaling that disrupts insulin sensitivity, amplifies inflammatory cascades, and disrupts cellular energy homeostasis. There is also a strong association between ER stress and autoimmune diseases, as it not only causes abnormalities in the function of immune cells but also may trigger an autoimmune response as well as an inflammatory response. ER stress is a root cause of disease, fueling chronic inflammation, autoantibody generation, and irreversible tissue damage Role and influence of ER stress in four common types of diseases. Genetic and metabolic abnormalities, inflammation, hypoxia, and other factors can induce ER stress and thus lead to disease. Cardiac pressure overload or ischemia triggers ER stress, leading to protein-folding dysfunction in cardiomyocytes and activation of the UPR, which increases metabolic disturbances, hypoxia, and inflammatory responses in the heart. ER stress reflects both adaptive and maladaptive effects in cardiovascular disease. Early activation of pathways such as the ATF6 or IRE1/XBP1 pathway promotes cytoprotection and restores ER homeostasis, whereas sustained PERK/CHOP signaling often leads to pathological remodeling, apoptosis, and clinical deterioration. ER dysfunction not only leads to protein-folding errors but also affects processes such as mitochondrial function, calcium homeostasis, and cellular autophagy, which in turn trigger neurodegeneration. The aggregation of β-amyloid and tau proteins triggers ER stress, leading to neuronal dysfunction and further aggravating cognitive impairment. Chronic ER stress exacerbates neurodegeneration by driving neuroinflammation, synaptic deficits, and apoptosis. In patients with obesity and type 2 diabetes mellitus, ER stress is often responsible for the impairment of pancreatic β-cell function and insulin secretion disorders, which leads to decreased glucose utilization and loss of pancreatic cell function. Activation of the UPR pathway inhibits normal pancreatic β-cell function and promotes an inflammatory response in adipose tissue. ER stress stems from metabolic overload, triggering maladaptive UPR signaling that disrupts insulin sensitivity, amplifies inflammatory cascades, and disrupts cellular energy homeostasis. There is also a strong association between ER stress and autoimmune diseases, as it not only causes abnormalities in the function of immune cells but also may trigger an autoimmune response as well as an inflammatory response. ER stress is a root cause of disease, fueling chronic inflammation, autoantibody generation, and irreversible tissue damage Atherosclerosis is a chronic inflammatory vascular disease characterized by the formation of plaques within the intima of blood vessels. 263 ER stress is a hallmark of advanced atherosclerosis, and research on understanding its pathogenesis and identifying biomarkers and therapeutic strategies is urgently needed. In 2001, Nonaka’s team first reported that taurine could resist atherosclerosis by blocking homocysteine-induced ER stress. 264 Mechanistically, the inhibition of GRP78 and PERK expression relieves ER stress, thereby restoring the secretion of extracellular superoxide dismutase, which protects the vessel wall. Recent studies have shown that fragile X mental retardation protein (FMRP) is induced by ER stress and that one of its sites is phosphorylated. 265 This site enhances the translational repression of FMRP binding to mRNA but inhibits macrophage cholesterol efflux and apoptotic cell clearance upon activation of IRE1. In contrast, pharmacological inhibition by the IRE1 kinase-specific inhibitor AMG-18 blocked IRE1 kinase-FMRP signaling and phenocopied the lack of FMRP in macrophages, preventing atherosclerosis progression. ox-LDL can elicit ER stress-mediated IRE1/XBP1-induced inflammatory responses in a calcium-dependent manner in the cytoplasm and is a key factor in the development and progression of atherosclerosis. 266 Recent studies revealed that the deletion of adipose TG lipase (ATGL) in endothelial cells resulted in the upregulation of basal and palmitate-induced ER stress, with significant changes in the associated factor XBP1. 267 Mechanistically, loss of ATGL leads to the production of ER stress in endothelial cells, which increases lesion size. ER stress enhances the proinflammatory response of endothelial cells, which leads to the accumulation of neutral lipids in the vasculature, thus contributing to the worsening of atherosclerosis. In 2018, the homocysteine-responsive ER protein (Herp) was used to understand the progression of atherosclerosis. 268 Lin et al. reported that the ATF6 axis of ER stress was significantly activated and induced a phenotypic transition in smooth muscle cells (SMCs) in mice fed a high methionine diet. However, in Herp-deficient mice, Lin et al. reported that atherosclerotic lesions were reduced in the aortic sinus and throughout the aorta; thus, the inhibition of Herp effectively prevented the development of atherosclerosis. Recently, C/EBPβ was shown to attenuate lipid-mediated ER stress and apoptosis. 269 C/EBPβ has potent inhibitory effects on ATF4 and ATF6 and has been shown to block the development of atherosclerosis and macrophage foam cell formation. Abe et al. reported a possible association between membrane-associated guanylate kinase with inverted structural domain structure-1 (MAGI1) and atherosclerosis. 270 They used microarray screening to reveal the critical role of MAGI1 in the ER stress response. The results showed that MAGI1 can regulate endothelial cell activation and form a complex with ATF6 to regulate ER stress and apoptosis, key molecular events in atherosclerosis. Moreover, the expression of XBP1, a hub molecule in this network, is downregulated without MAGI1. 271 In addition, researchers have shown that MAGI1 can directly bind to ATF6, a transmembrane protein involved in the ER stress response, and regulate the nuclear translocation of ATF6, which also validates the link between MAGI1 and atherosclerosis. ox-LDL is also frequently used as a classical factor to mimic atherosclerosis in vitro. Aldehyde dehydrogenase 2 (ALDH2) has a unique function in inhibiting atherosclerosis progression by attenuating ER stress and SMC apoptosis. 272 Experimentally, ox-LDL was found to promote the upregulation of the ER stress marker PERK, suggesting that ER stress plays an important role in the development and progression of atherosclerosis. Recent findings by Kaw et al. suggest that smooth muscle cell (SMC) α-actinin missense mutations can lead to increased atherosclerosis. 273 Mutations in ACTA, the gene encoding SMC, caused elevated intracellular cholesterol levels, inducing ER stress, specific activation of PERK, and a significant increase in the activities of ATF4 and KLF4 in downstream signaling. ER stress enhances atherosclerosis-associated SMC phenotypic regulation, including increased plaque formation. In addition, a comparative study revealed that CHOP, a downstream factor of PERK, may play a role in the progression of atherosclerotic plaques. 274 Its activation in unstable plaques was confirmed by the finding of significantly elevated immunostaining levels of the CHOP factor, which induces ER stress that increases SMC and macrophage apoptosis. Recently, insulin receptor substrate 1 (IRS-1) has been used to study the effects of ox-LDL exposure on atherosclerosis. 275 In the ox-LDL-induced disease model, the expression of the ER stress biomarkers CHOP and eIF2α was significantly lower in endothelial cells than in those without IRS-1. IRS-1 inhibited ER stress and apoptosis by activating the AKT1/FOXO1 axis, thereby preventing ox-LDL-induced atherosclerosis. In addition, IRS-1 significantly enhanced the proliferative activity of endothelial cells while inhibiting apoptosis, suggesting that IRS-1 can potentially resist ER stress and atherosclerosis development. Myocardial I/R refers to the pathological process in which the ischemic myocardium can regain normal perfusion. The ER, as a reservoir of calcium ions, has gradually become the focus of ameliorating I/R injury. In 2006, Martindale et al. identified for the first time a cardioprotective mechanism of ER stress during I/R. 276 The ATF6 branch of the UPR is activated in the heart, and its induced expression of GRP78 and GRP94 better restores I/R function and significantly reduces necrosis and apoptosis. Recent studies have shown that ALDH2 can be used as a drug target to alleviate I/R injury and that the inhibition of ER stress plays a key role in this mechanism. 277 ALDH2 deficiency leads to the upregulation of ER stress-related genes, including CHOP and GRP78, which exacerbates myocardial I/R injury. Yang et al. reported that ALDH2 effectively removes endogenous aldehydes, which can consequently attenuate the ER stress-induced formation of neutrophil extracellular traps (NETs), thereby preventing I/R injury. In a rat experiment, the sarcoplasmic reticulum Ca2+ ATPase pump (SERCA2a) ameliorated myocardial I/R injury in rats by inhibiting ER stress. 278 Given the significantly lower prevalence of CHD in premenopausal women, estrogen upregulates the expression of SERCA2a, which inhibits the expression of the ER stress-related proteins CHOP, CRT, caspase-12, and GRP78. These findings provide new potential targets for drug development to ameliorate I/R injury. However, not all ER stress is deleterious, as Jin et al. revealed the protective effect of the ATF6-mediated ER stress response against I/R injury. 118 Blocking the signaling pathway of ATF6 resulted in increased damage to and decreased function of mouse cardiomyocytes after I/R. The reason for this is that increased ROS mainly causes cardiac I/R injury, but ATF6 induces a variety of antioxidative stress genes, such as catalase, which can reduce ROS. In addition, the ATF6-dependent increase in BiP may also be related to its ability to protect tissues such as the heart from I/R injury. ATF6 branching adaptively reprograms endoplasmic membrane protease homeostasis by inducing a wide range of protective response genes, thereby reducing cardiomyocyte death and providing cardiac protection against I/R injury. 279 This novel mechanism suggests that the ER stress response reduces myocardial I/R injury, validating the potential of the pharmacological activation of ATF6 in the treatment of I/R injury. MI is a disease in which the myocardium is necrotic due to acute obstruction of the coronary arteries, resulting in insufficient blood supply to the corresponding myocardial region. 280 Correction of ER stress allows the cardiomyocyte reticular network to restore energetic and/or trophic homeostasis and avoid cell death. This property is an important target for the treatment of MI. 281 In 2006, Thuerauf et al. demonstrated for the first time that hypoxia-induced ER stress may be involved in myocardial protection. 282 They reported that, compared with healthy hearts, hearts of MI model mice presented increased GRP78 expression in cardiomyocytes near the infarct area, which promoted cardiomyocyte survival. Liu et al. reported that all 3 UPR branches are activated after MI and that pharmacological inhibition of PERK prevents the downregulation of cardiac Na+ and K+ channels and reduces deleterious electrical remodeling. 283 Therefore, inhibition of the PERK axis of the UPR prevents selective cardiac ion channel downregulation and protects against MI, a novel therapeutic strategy. 284 Similarly, the inhibition of CHOP, a factor downstream of PERK, attenuated ventricular remodeling after acute MI. 285 A recent study demonstrated for the first time that MI induces significant adipocyte ER stress and endocrine dysfunction by releasing small extracellular vesicles enriched in the miR-23-27-24 cluster. 133 ER degradation-enhancing alpha-mannosidase-like protein 3 (EDEM3) was identified as a downstream factor of ATF6 and MI-induced activation of PERK/CHOP and ATF6/EDEM in adipocytes. The administration of GW4869 or cardiomyocyte-specific miR-23-27-24 cluster sponges attenuated adipocyte ER stress in animal experiments, which may be an effective therapeutic pathway to ameliorate MI. Mali et al. reported that initiating tyrosine kinase activity of epidermal growth factor receptor (EGFR) may contribute to the adverse effects of ER stress in patients with diabetic MI. 286 In addition, the results showed that inhibition of EGFR significantly reduced infarct size and ER stress induction, suggesting that ER stress is a downstream mechanism of EGFR and that its use as a target may provide a new therapeutic strategy for MI injury. The protective effect of ATF6 has also been demonstrated in MI. Toko et al. administered an ATF6 inhibitor to mice and reported that the survival rate at 14 days after MI was reduced and that cardiac function was further decreased. 287 Experiments have demonstrated that pharmacological inhibition of ATF6 leads to left ventricular dilatation and decreased cardiac function in the mouse heart, confirming the cardioprotective capacity of activating the ER stress response factor ATF6 under pathological conditions. 288 HF is a disease caused by a malfunction of the pumping function of the heart, resulting in the inability of the heart to meet the basic metabolic needs of the entire body. Over the past decade, ER stress has emerged as an important mechanism in the pathogenesis of cardiovascular diseases, including HF. 289 In 2004, Okada et al. reported for the first time that CHOP-dependent pathways are activated in failing hearts, suggesting that prolonged ER stress may lead to cardiomyocyte apoptosis, resulting in HF. 23 Protective ER stress is sometimes beneficial in pressure overload-mediated cardiac remodeling. The specific and protective effects of IRE1 on HFs were first demonstrated by Steiger et al. 290 Transient activation of IRE1/XBP1 in mouse cardiomyocytes preserved cardiac function and reduced the fibrotic area, and this strong but transient adaptive ER stress response resulted in attenuated inflammatory and pathological gene expression. Binder et al. reported that p21-activated kinase 2 (Pak2)-deficient mice exhibit defective ER stress and cardiac dysfunction. 291 Gene array analysis revealed that Pak2 regulates ER function via the IRE1/XBP1 axis by inhibiting protein phosphatase 2A activity, a protective ER stress response. The activation of Pak2 restores ER function and thus protects the heart from failure; thus, Pak2 could serve as a novel therapeutic target for the cardioprotective ER stress response. The PERK arm exerts deleterious effects primarily on HFs, increasing the risk of sudden death in patients by increasing mRNA degradation, leading to a decrease in Na+ channels, proteins, and currents. 292 The angiogenic factor AGGF1 can modulate ER stress-related signaling by inhibiting the activation of PERK/eIF2α/ATF4/CHOP, which reduces cardiac cell death and attenuates HF. 293 Atorvastatin was shown to be very effective in inhibiting CHOP as well as other ER stress components, including GRP78, caspase-12, and DDIT3, to protect cardiomyocytes. 294 These findings support the potential therapeutic value of targeting ER stress to reduce cardiac remodeling in HF. Recently, ER stress was shown to induce cardiac dysfunction through altered cardiomyocyte structure and mitochondrial function. 295 In mouse experiments, ER stress in cardiomyocytes led to a significant reduction in the expression of PGC-1α, a major regulator of mitochondrial biogenesis, which impaired mitochondrial calcium ion uptake and excitation‒contraction coupling. This study demonstrated that mitochondrial calcium ion uptake dysfunction and metabolic abnormalities are key factors in ER stress-induced HF. These results suggest that IRE1 and PERK play crucial roles in maintaining calcium homeostasis, endoplasmic network integrity, and cell survival under stress and are promising options for treating HF. Overall, ER stress plays a dual role in the pathogenesis of cardiovascular diseases. While ER stress is triggered by pathological factors such as metabolic dysregulation, oxidative stress, and inflammation, it acts as a downstream manifestation of these insults. It also exacerbates disease progression by amplifying inflammatory damage, oxidative stress, and apoptosis, thereby establishing a vicious cycle of cellular dysfunction. Notably, the UPR has both adaptive and maladaptive effects in cardiovascular diseases: early activation of pathways such as the ATF6 or IRE1/XBP1 pathways can promote cytoprotection and restore ER homeostasis, whereas sustained PERK/CHOP signaling often drives pathological remodeling, apoptosis, and clinical deterioration. Experimental evidence, including pharmacological inhibition of ER stress regulators and genetic modulation, such as CHOP-deficient models, highlights ER stress as both a consequence of upstream pathologies and a contributor to disease progression. Thus, targeting specific UPR branches to modulate ER stress represents a promising therapeutic strategy, balancing its dual roles in mitigating cardiovascular disease severity while preserving adaptive cellular responses. Neurodegenerative diseases worsen over time, with a progressive loss of nerve cells or a gradual loss of function. 296 These diseases include Alzheimer’s disease (AD), PD, and Huntington’s disease (HD). The consequences of ER stress may vary greatly depending on the disease context and alterations in the UPR signaling pathway, and targeting the UPR may have different or even opposing effects on disease progression, which holds promise for interventions to alleviate neurodegenerative diseases. 297 This section explores recent advances in the functional link between ER stress and neurodegeneration (Fig. 5 ). AD is a degenerative disorder of the central nervous system, and the risk of developing this disease increases with age. 298 Increased markers of UPR activation are widespread in the brain tissue of AD patients. 299 In 1999, Katayama’s team reported for the first time how ER stress caused by the presenilin-1 (PS1) gene affects AD. 20 PS1 mutations lead to reduced levels of GRP78 in the brains of AD patients, which increases the susceptibility of nerve cells to apoptosis. ER stress is usually prominent in the early cytopathology of AD. Lee’s team used RT‒PCR experiments to demonstrate increased splicing of the UPR transcription factor XBP1 in the brain temporal cortex of AD patients. 300 A recent study revealed that XBP1 can ameliorate AD by improving synaptic function and protein homeostasis, and that moderate activation restores the levels of several synaptic proteins and factors involved in the regulation of the actin cytoskeleton and axon growth. 301 XBP1 not only reduces the beta-amyloid load in AD mice but also successfully improves their cognitive deficits, which results in the establishment of adaptive and repair programs. Most phosphorylated PERK and eIF2α are located in the pyramidal cell band of Ammon’s horn and are often detected in the brains of AD patients. 302 PERK and eIF2α are widely activated in the hippocampus, which increases the risk of disease. Yang and colleagues reported a detrimental effect of chronic PERK signaling on synaptic function in an AD mouse model because PERK exacerbates de novo protein synthesis deficits and cognitive deficits caused by metabotropic glutamate receptor 5 damage. 303 Recent studies suggest that 2-deoxyglucose may be a promising drug for treating memory dysfunction in AD. 304 Glucose restriction reduces ER stress in neurons by decreasing ATF4 expression, leading to increased gene transcription related to plasticity, cognitive resilience, and protein homeostasis. Baleriola et al. reported that ATF4 proteins and their transcripts are more frequently expressed in axons in the brains of AD patients. 305 However, maintaining PERK/eIF2α/ATF4 expression at low levels can protect neuronal cells, demonstrating the positive role of the moderate UPR in intraaxonal translation during neurodegeneration. PD is a disorder characterized by motor dysfunction and eventual progression to cognitive dysfunction and involves more complex protein aggregation than does AD. 306 Abnormal UPR signaling is a distinctive feature of PD. In 2001, Chun et al. elucidated for the first time the pathogenic mechanism by which chronic exposure to manganese induces PD, which is attributed to the elevated levels of BiP in the ER stress response induced by manganese, leading to cell death in nigral dopaminergic neurons. 307 Early studies revealed that mild ER stress protects the seminal system in PD mice via a mechanism in which moderate activation of the IRE1/XBP1 pathway triggers autophagic responses in vivo. 308 This protection increases resistance to the exogenous apoptotic injury required for PD neuroprotection. However, in most cases, sustained ER stress is the causative agent of PD. Zeng et al.‘s study of thioredoxin-1 (Trx-1) revealed that its downregulation exacerbated PD, which was attributed mainly to the activation of IRE1-induced ER stress by 1-methyl-4-phenylpyridinium ion (MPP(+)) due to the downregulation of Trx-1. 309 A recent report revealed that Trx-1 can also inhibit IRE1 activation in PD by targeting heat shock protein 90 (Hsp90) and phosphorylated cell division cycle 37 (p-Cdc37) chaperone complexes. 310 These results suggest that Trx-1 may be a potential target for the treatment of PD. In addition, El Manaa’s team reported that XBP1 expression is elevated in the brains of PD patients, possibly due to a combination of ER stress and mitotic dysfunction. 311 The activation of XBP1 upregulates PTEN-induced kinase 1 (PINK1) expression in neuronal cells at the transcriptional level, which leads to the disruption of mitotic control under PD conditions. Misfolded glucocerebrosidase protein induces ER stress and subsequent UPR responses, impairing the autophagy-lysosomal pathway. This leads to the accumulation and diffusion of α-synuclein and promotes neurodegenerative changes leading to PD. 312 In addition, α-syn tends to accumulate in the ER lumen and induce ER stress, possibly through aberrant associations with chaperone proteins. 313 α-syn inhibits the incorporation of ATF6 into COPII vesicles, and the reduction in ATF6 signaling through this physical relationship leads to a decrease in ERAD function and an increase in proapoptotic signaling. A recent study revealed that leucine-rich repeat kinase 2 protein (LRRK2) impairs calcium homeostasis in the ER environment of astrocytes, leading to intense ER stress. 314 The mechanism involved is increased mRNA and protein levels of PERK/CHOP, which further increase the toxicity of α-syn and may contribute to PD development. A further study of LRRK2 by Yao et al. revealed that it can also interact with thrombospondin-1/transforming growth factor beta1 (THBS1/TGF-beta1) to induce ER stress. 315 The significant upregulation of the related factors ATF4/CHOP and GRP78 revealed a role for LRRK2 in inducing ER stress, and intense stress ultimately led to neuron death in PD patients. HD is an autosomal dominantly inherited neurodegenerative disease. 316 The disease was discovered by the American medical scientist George Huntington in 1872. 317 Moderate control of the intensity of the UPR can effectively improve HD via Huntington’s protein accumulation. In 2002, Nishitoh and colleagues first identified the role of ER stress in HD. 318 PolyQ, which is pathogenic in length, activates ASK1 through the IRE1 pathway during ER stress, which activates JNK and induces neuronal cell death. Huntington’s protein continuously activates IRE1 signaling during ER stress in the striatum, triggering neuronal loss and leading to the adverse effects of HD. 319 However, Hyrskyluoto et al. reported that ubiquitin-specific protease 14 (Usp14) could inhibit Huntington’s protein buildup, which was accompanied by a reduction in ROS and ER stress. These findings suggest that Usp14 has a role in counteracting Huntington’s protein toxicity. Vidal et al. reported that XBP1 deficiency was associated with improved neuronal survival and motor performance in cellular and animal models of HD. 320 XBP1 expression leads to the impairment of its downstream factor, Forkhead box O1 (FoxO1), and the inhibition of FoxO1, a key transcription factor that regulates neuronal autophagy, leads to diminished resistance to HD and exacerbates this condition. Therefore, targeting the UPR transcription factor XBP1 by regulating autophagy may be a feasible way to prevent HD. Huntington protein fragments can alter ER morphology, leading to ER expansion and a stress response. 321 Experiments revealed that the abundance of the ER stress signal ATF6 and the phosphorylation of eIF2α were significantly elevated in the striatum of HD mice. When the processing and transcriptional activity of ATF6 are increased, the prosurvival UPR function of striatal neurons is increased. 322 Naranjo’s team determined that silencing downstream regulatory element antagonist modulators can induce ATF6 signaling activation to promote early neuroprotection in HD. In conclusion, emerging evidence highlights the pivotal role of ER stress in neurodegenerative diseases. ER stress is a root cause of neuronal dysfunction and is initiated by the accumulation of misfolded proteins that disrupt proteostasis and activate the UPR. Chronic ER stress exacerbates neurodegeneration by driving neuroinflammation, synaptic deficits, and apoptosis, as evidenced by the dysregulation of UPR pathways in these disorders. Therapeutic interventions targeting ER stress modulation, such as enhancing adaptive UPR components or suppressing maladaptive signaling, hold promise for alleviating neurodegenerative diseases. Thus, ER stress serves both as a mechanistic origin of neurodegenerative disease initiation and a dynamic contributor to pathological cascades, positioning it as a critical therapeutic target and biomarker for neurodegenerative disorders. Metabolic diseases are a group of disorders characterized by metabolic abnormalities. 323 These diseases are caused by the accumulation or deficiency of certain metabolic substances, such as sugars, fats, and proteins, when biochemical processes in the body are impaired. The function of the ER as a site for the exchange of ions, lipids, and metabolites is particularly critical. 324 This chapter describes the role of ER stress in three common metabolic diseases, namely, IR, type 2 diabetes (T2D), and obesity (Fig. 5 ). IR refers to the weakening of the physiological role of insulin in the body, mainly manifested as a decrease in the efficiency of glucose uptake and utilization by insulin, and is a common pathological mechanism for the development of a variety of metabolism-related diseases. 325 Recent findings suggest that ER protein misfolding and subsequent activation of UPR signaling play key roles in the pathogenesis of IR. 326 In 2004, Ozcan et al. demonstrated for the first time in mice that deficiency of the transcription factor XBP1, which regulates the ER stress response, results in IR. 22 In a recent study, Yue’s team analyzed the effect of triphenyl phosphate (TPHP) on hepatic glucose homeostasis. 176 This study revealed that TPHP exposure induced ER stress, significantly increasing the expression levels of XBP1, CHOP, and ATF4. The TPHP-induced impairments in glucose uptake and glycogen synthesis were reversed by the use of ER stress inhibitors, and both postprandial glucose levels and insulin sensitivity were partially restored. These results suggest that TPHP induces hepatic ER stress and IR in a concentration-dependent manner. Obesity is a major causative factor of IR. Functional changes in adipose tissue were examined by mimicking obesity with a high-fat diet, and the upregulation of CHOP expression was found to increase ER stress. 327 In CHOP-deficient mice, despite similar macrophage infiltration, adipose tissue macrophages tend to be anti-inflammatory with M2-type polarization, and M2-type macrophages suppress inflammation and improve insulin sensitivity by secreting Th2 cytokines. In vitro experiments revealed that CHOP knockdown reversed the ER stress-induced downregulation of IL-13 and lipocalin, confirming that CHOP regulates adipocyte function and the microenvironment through cell-autonomous mechanisms. In addition, miR-379 can play an important role in high-fat diet-induced IR through mitochondrial dysfunction, the PERK/CHOP pathway of ER stress, and impaired angiogenesis. 328 In recent studies, ER-localized methionine sulfoxide reductase B3 (MsrB3) has been shown to protect cells from oxidation and ER stress; thus, MsrB3 may be a potential target for treating diet-induced IR. 329 T2D, the most common type of diabetes, is a chronic disease caused by insufficient or less efficient use of insulin. 330 Studies in recent years have shown that ER stress-related proteins are also involved in the pathogenesis of T2D, inducing different degrees of IR and hyperglycemia caused by insulin secretion dysfunction. 331 In 2001, Harding’s team first reported that PERK was highly expressed in the mouse pancreas and increased the phosphorylation of eIF2α, leading to an increase in ER stress-induced pancreatic cell death, which promoted the development of T2D. 332 Nie and colleagues reported that procyanidin B2 (PCB2) attenuated three pathways (IRE1, ATF6, and PERK) associated with high glucose-induced ER stress in human vascular endothelial cells, which may constitute a novel strategy for treating T2D. 333 Recent studies have shown that abnormal vascular endothelial function in the offspring of rats with diabetes mellitus is associated with increased ER stress. 334 The mechanism may involve the downregulation of 5′ adenosine monophosphate-activated protein kinase (AMPK) signaling, an upstream regulator of ER stress, which increases the expression of IRE1, ATF6, and PERK/elF2α, leading to metabolic function abnormalities. Yalcinkaya et al. demonstrated that sustained ER stress can lead to loss of pancreatic cell function through mouse pancreatic islet B-cell studies. 335 High-density lipoprotein (HDL) alone can prevent the onset of T2D via the elimination of the splicing of the ER stress-related gene XBP1, which in turn has antidiabetic effects by inhibiting ER stress. Physical activity positively modulates the metabolic response in diabetic patients, which is attributed to attenuating ER stress and improving insulin signaling. 336 T2D-induced mitochondrial damage and worsening of ER stress can be attenuated by physical exercise, with ATF6 being the most pronounced change, and it is expected to be a new therapeutic target for T2D. Early studies revealed that activation of the PERK/CHOP pathway in response to ER stress exerted a proapoptotic effect on pancreatic islet B cells. 337 The protein expression levels of CHOP and BiP are also significantly increased in T2D patients with islet B-cell failure. 338 T2D is triggered by impaired islet B-cell function due to ER stress, leading to absolute or relative insulin secretion deficiency. In addition, curcumin enhances exercise-induced attenuation of ER stress, mainly by reducing the expression levels of BiP and CHOP. 339 Zhang’s team identified a new potential target for T2D therapy. 340 Thyroid adenocarcinoma-associated protein (THADA) is strongly activated in T2D patients, contributing to sustained ER stress in pancreatic islet B cells, followed by activation of the PERK/ATF4/CHOP axis, which exacerbates apoptosis. The most direct manifestation of this is that knockdown of the PERK gene in mice improves the progression of T2D. 341 Selenium nanodots (SENDs) are expected to act as antioxidants to rescue islet B cells from T2D patients by restoring mitochondrial autophagy and attenuating ER stress. 342 SENDs strongly inhibit the transcription of PERK/eIF2α/ATF4/CHOP pathway-associated mRNAs by increasing glutathione peroxidase 1 (GPX1) expression, which can abrogate ER stress very efficiently and thus maintain the functional stability of islet B cells. The interaction of the PERK pathway with T2D has been explored, with IRE1 and ATF6 awaiting more studies in the future. Obesity is defined as the amount of stored fat in the body that exceeds 20% or more of the ideal body weight and is a chronic metabolic disease caused by the interaction of multiple factors, including genetic and environmental factors. 343 Over the past two decades, a large body of evidence has supported the role of adipose tissue ER stress in human metabolic diseases and pointed to the possibility of treating obesity and related diseases. In 2004, Ozcan’s team first elucidated the mechanism of obesity-induced ER stress. 22 This study revealed increased phosphorylation of PERK and eIF2α in high-fat diet-induced obese mice, which demonstrated the production of ER stress. Adipose tissue macrophages are key players in metabolic inflammation, and macrophage IRE1 has been shown to promote their selective activation and regulate M1–M2 polarization. 344 Bone marrow-specific IRE1 activation manifests as sustained ER stress, which damages brown adipose tissue activity, thereby inducing the development of obesity. Leptin secretion plays an important role in regulating hypothalamic circuits and metabolism, directly affecting obesity. 345 Recently, Park performed a new analysis of the mechanism of action of leptin. Leptin-deficient mice exhibit elevated hypothalamic ER stress, including that of XBP1, ATF6, ATF4, and GRP78, as early as post-natal day 10. 346 After the administration of the ER stress inhibitor taurine deoxycholic acid, metabolic diseases and body weights of the mice significantly improved. In obese patients, the expression levels of the ER stress-related proteins ATF6 and CHOP are successfully reduced via a low-calorie diet program, which is accompanied by the restoration of calcium ion pools. 347 This finding reflects the attenuation of chronic ER stress and mitochondrial dysfunction and has the potential to serve as a potential target for the treatment of metabolic complications of obesity. Moderate caloric restriction modulates PERK/EIF2A/CHOP expression levels in subcutaneous adipose tissue, reducing ER stress and ameliorating obesity-related metabolic changes. 348 Therefore, weight reduction through caloric restriction may be a generally acceptable strategy to reduce ER stress in obese patients while preventing other complications. A study by Tirosh et al. also revealed increased hepatic ER stress in mice fed a high-fat diet and increased expression of connexin 43 (Cx43) in response to obesity. 347 Chronic ER stress in hepatocytes induces the upregulation of Cx43 through the activation of GRP78 and eIF2α, which triggers cell‒cell coupling, leading to ER stress in other cells due to ER dysfunction. These results suggest that intercellular transmission of hepatic ER stress in obese patients may interfere with systemic metabolic homeostasis. These findings emphasize the importance of ER stress-related pathways in metabolic regulation early in life. In summary, the intricate interplay between ER stress and metabolic disorders underscores its dual role as both a pathogenic driver and a consequential hallmark of conditions. ER stress arises from metabolic overload, triggering maladaptive UPR signaling that disrupts insulin sensitivity, amplifies inflammatory cascades, and compromises cellular energy homeostasis. While ER dysfunction originates from imbalances in nutrient metabolism, it subsequently manifests as a pathological feature, perpetuating cycles of metabolic dysregulation. Interventions aimed at restoring ER protease inhibition through UPR regulation, enhanced redox balance, or regulation of stress-reactive genes are promising pathways for reducing disease severity. Elucidating the temporal and tissue-specific dynamics of ER stress in metabolic contexts remains critical for developing targeted therapies to address these escalating global health challenges. Autoimmune diseases are disease states resulting from an immune response by the body’s immune system against its components, including RA, multiple sclerosis (MS), and inflammatory bowel disease (IBD). 349 These diseases usually involve all body systems, including blood, joints, muscles, bones, and soft tissues around the joints. 350 Once diagnosed, patients should be treated promptly to avoid further progression of the disease, which can damage tissues, organs, or systems. 351 In recent years, it has been reported that ER stress plays a crucial role in the pathogenesis of autoimmune diseases. ER stress is an important mediator of immune cell dysregulation, the activation of proinflammatory pathways, and cellular tissue damage. 13 Understanding this relationship may provide new avenues for targeted therapies to treat this disease (Fig. 5 ). RA is an autoimmune disease that is pathologically based on synovitis and may eventually lead to joint deformity. 352 ER stress has been found to have an important effect on RA and may be involved in the pathogenesis of RA through synovial cell proliferation and proinflammatory cytokine production. 353 In 2004, Bodman-Smith and colleagues demonstrated for the first time that the ER stress protein BiP is involved in the pathogenesis of RA, as BiP was found to be present in the serum of RA patients and to stimulate synovial T-cell proliferation. 24 To diminish the pathogenicity of fibroblast-like synoviocytes (FLSs), Qi’s team used zinc ferrite nanoparticles targeting fibroblast-activating proteins (FAP-ZF-NPs) in an attempt to treat RA. 354 It enhances FLS apoptosis by appropriately activating the ER stress response and mitochondrial damage through the IRE1/XBP1 and PERK/ATF4/CHOP pathways. In addition, due to the ferrous nature of the FAP-ZF-NPs, the magnetothermal effect could further increase ER stress and mitochondrial injury to improve therapeutic outcomes. However, strong ER stress needs to be suppressed; otherwise, an inflammatory response is generated to exacerbate RA. For the first time, Savic’s team demonstrated that XBP1 activation is associated with RA and that this activation is dependent on toll-like receptors (TLRs). 355 Recent studies have shown that ER stress enhances the expression of inflammatory cytokines and vascular endothelial growth factors in synovial fibroblasts (SFs) stimulated by different TLR ligands, leading to persistent inflammation in RA patients. 356 Rational inhibition of XBP1 reduces the expansion of T helper (Th)1/Th17 cells, a pathway that may serve as a therapeutic target for RA. In addition, the expression of DERL3, an ER-related degradation component in the SF, is elevated in RA patients, and its inhibition can prevent the activation of NF-κB and attenuate the inflammatory response. 357 Furthermore, Yoo et al. reported that synoviocytes in RA express relatively high levels of GRP78 and that the inhibition of Grp78 transcripts increases synoviocyte apoptosis, which has an inhibitory effect on arthritis. 358 MS is a chronic inflammatory demyelinating autoimmune disease of the central nervous system in which the immune system is involved in its development and progression. 359 Although some studies have shown that ER stress plays a role in MS, research in this area has not been sufficient in recent years. 360 In 2006, Lin et al. first elucidated the role that interferon-gamma-mediated ER stress plays in MS. 361 Interferon-gamma leads to PERK dysfunction, which severely inhibits myelin regeneration and has a deleterious effect. The activation of ER stress, especially the eIF2α/CHOP pathway, is detected in retinal ganglion cells (RGCs) at the early stage of MS. 362 Sustained ER stress triggers neuronal and glial apoptosis and may also release self-antigens to stimulate further autoimmune responses. Significantly increased RGC survival was found in animal experiments in CHOP knockout mice and mice overexpressing XBP1, suggesting a neuroprotective effect of eIF2α/CHOP inhibition and XBP1 activation against MS. To alleviate the neuropathic pain caused by MS, Yousuf et al. reported that ER stress in neurons may be one of the sources of pain. 363 In MS tissues, the protein levels of XPB1, as well as BiP, are increased, so an attempt was made to inhibit ER stress via the use of 4-PBA. 364 The phosphorylation levels of eIF2α, CHOP, and XBP1 were significantly reduced after the administration of 4-PBA, which effectively alleviated ER stress to reduce nociceptive hypersensitivity. IBD is an idiopathic bowel disease involving the ileum, rectum, and colon. 365 ER stress was found to regulate the function of immune cells by activating the UPR. 366 In 2006, Shkoda’s team first reported elevated levels of GRP78 expression in the intestinal epithelial cells of IBD patients, suggesting the activation of the ER stress response. 367 In addition, they reported that IL-10 could inhibit the mechanism of the inflammation-induced ER stress response by regulating ATF6 nuclear recruitment to the GRP78 gene promoter, which provides a new strategy for the treatment of IBD. Group 3 innate lymphoid cells (ILC3s) are commonly found in the gut and have been shown to be correlated with IBD in a recent study. 368 Appropriate activation of the IRE1/XBP1 pathway in ILC3s contributes to their cytokine expression and maintenance of intestinal homeostasis; additionally, IRE1 deficiency results in intestinal tissues being more susceptible to infection and colitis. In a recent report, Ke and colleagues screened microbiome molecules with UPR activity based on XBP1, including ER stress response inducers (acylated dipeptide aldehydes and bisindolylmethane derivatives) and inhibitors (soraphen A). 369 The experimental results suggest that these metabolites may contribute to gut ER homeostasis and provide mechanistic insights into the relationship between the microbiome and inflammatory diseases. Like in other diseases, ATF6 also plays a protective role in IBD. Ranjan et al. demonstrated that UPR-associated responses can orchestrate the innate immune response, where ATF6 deficiency leads to impaired intestinal bacterial clearance and increased risk of infection and inflammation. 370 In contrast, aberrant activation of the UPR can lead to immune cells in the gut exhibiting proinflammatory properties, increasing the release of inflammatory factors and exacerbating inflammatory responses in the gut. 371 ER stress was found to promote the production of proinflammatory cytokines such as IL-6. 372 The increased protein products of CHOP and GRP78 in IBD patients indicate that ER stress is activated, a state that drives DCs to become proinflammatory cells, as evidenced by increased expression of IL-6, which plays an important role in the inflammatory process of IBD. In addition, ER stress leads to abnormal protein folding in gastrointestinal cells, thereby affecting the integrity of the intestinal barrier. Al-Shaibi et al. reported that anterior gradient 2 (AGR2) deficiency leads to mucin misfolding and that intense ER stress induces mucus barrier defects, triggering IBD. 373 AGR2 deficiency may disrupt mucin 2 (MUC2) processing and impair ER stress regulation, as evidenced by the high expression of GRP78 in patients’ intestinal and gastric mucosa. Microbial changes in the gut are closely related to the onset and progression of IBD, and ER stress may alter the microbial composition by affecting the intestinal environment. However, this type of study is still relatively rare. In summary, accumulating evidence positions ER stress as a fundamental etiological driver rather than a consequence of autoimmune diseases. ER stress directly initiates and perpetuates pathological cascades by disrupting immune homeostasis through the activation of inflammatory signaling pathways and impairing critical cellular functions. In RA, unresolved ER stress promotes synovial fibroblast hyperactivation and proinflammatory cytokine production; in MS, it compromises oligodendrocyte-mediated myelin repair; and in IBD, it destabilizes intestinal barrier integrity and amplifies mucosal inflammation. These mechanisms underscore ER stress as a root cause of disease, fueling chronic inflammation, autoantibody generation, and irreversible tissue damage. Importantly, therapeutic interventions targeting ER stress mediators and UPR components have the potential to interrupt disease progression by resolving stress-induced immune dysregulation. Thus, ER stress represents a central pathogenic hub in autoimmune disorders, offering actionable molecular targets for precision therapies aimed at restoring immune tolerance and halting organ damage.

ER stress is an important mechanism by which cells respond to environmental changes and physiological stress. As an important organelle in the cell, the ER is responsible for synthesizing, folding, and modifying proteins and is also involved in lipid synthesis and calcium storage functions. When cells encounter unfavorable environments (e.g., hypoxia, nutritional deficiencies, pathogen infections, etc.) or intrinsic defects (e.g., protein-folding errors), the function of the ER may be impaired, leading to ER stress. It affects cell survival and is closely related to the occurrence and development of many diseases. In 1977, scientists first discovered glucose-regulated protein 78 (GRP78), also known as binding immunoglobulin protein (BiP), and focused on characterization in the ER. 14 Research on ER stress began in the 1990s, with initial studies focusing on how ER dysfunction affects the physiological state of cells. 15 In 1992, the discovery of transcription factors associated with ER stress opened the study of the UPR. 16 Three key proteins involved in the UPR were successively discovered in mammalian cells from 1998--1999. 17 – 19 These discoveries laid the foundation for subsequent studies revealing the important effects of ER stress on processes such as cell survival, death, and autophagy. Immediately afterward, the first functional study linking ER stress to neurodegenerative diseases reported that neurons are less tolerant to ER stress and that sustained activation is closely associated with neuronal apoptosis. 20 In 2002, with further research, the role of ER stress in cancer was gradually recognized. 21 Tumor cells usually experience high levels of ER stress in the microenvironment because they need to synthesize large amounts of proteins for rapid proliferation. The UPR helps tumor cells adapt to this stress to some extent, but prolonged ER stress may lead to cell death. Therefore, many researchers have focused on promoting tumor cell death by regulating the ER stress response. Research in this area has provided new ideas for cancer treatment. In 2004, research on ER stress made significant advances in a variety of diseases. First, ER stress was found to be a central feature of peripheral insulin resistance and type 2 diabetes mellitus, which play important roles in insulin secretion and fat metabolism. 22 Metabolic diseases can lead to ER dysfunction and affect insulin synthesis and secretion. Research in this area has provided new ideas for the treatment of metabolic diseases such as diabetes, suggesting that improving ER function may help to restore a normal metabolic state. In addition, ER stress is associated with cardiovascular diseases, and long-term stress can lead to cardiomyocyte apoptosis during the progression from cardiac hypertrophy to failure, suggesting that regulating ER stress may be a therapeutic strategy for cardiovascular diseases. 23 Furthermore, ER stress was first found to be associated with autoimmune diseases by studying the antibody response to the human stress protein BiP in patients with rheumatoid arthritis (RA). 24 Studies have shown that ER stress is involved in inflammatory responses and immune cell dysfunction and may lead to autoantigen exposure, which triggers an autoimmune response. In 2006, drugs targeting ER stress-related pathway inhibitors were first developed, such as 4-phenyl butyric acid (4-PBA), which was used to treat Parkinson’s disease (PD). 25 In 2007, Lin’s team revealed differences in the dynamics of different signaling branches in the ER stress-triggered UPR. The activities of IRE1 and ATF6 decrease under sustained stress, whereas the PERK pathway, including the sustained expression of the proapoptotic factor CCAAT/enhancer-binding protein homologous protein (CHOP), remains active, leading to a shift in the cellular response from protection to apoptosis. Cell survival was significantly enhanced by artificially prolonging IRE1 activity, suggesting that temporal regulation of UPR signaling is critical in determining cell life and death. 26 In 2008 and 2009, two studies revealed a novel mechanism linking ER stress to obesity. Overnutrition triggers obesity by inducing ER stress in the hypothalamus and activating the IKKβ/NF-κB signaling pathway, leading to central insulin and leptin resistance. 27 Reducing ER stress through genetic intervention or chemical chaperones (e.g., PBA and TUDCA) significantly restores leptin sensitivity and ameliorates obesity, and these studies suggest that targeting ER stress is a novel strategy for the treatment of obesity and related metabolic diseases. 28 In 2010, new progress was made in the application of ER stress in tumor therapy. In the hypoxic environment of tumors, ER stress transcriptionally activates the autophagy genes MAP1LC3B and ATG5 through the PERK/CHOP signaling axis, which enhances the hypoxia tolerance and radioresistance of tumor cells. 29 In 2011, a novel IRE1 small molecule inhibitor, STF-083010, was developed for the treatment of multiple myeloma (MM) and has shown significant antitumor activity. 30 In 2012, a PERK inhibitor, GSK2606414, and two IRE1 inhibitors, 4μ8C and MKC3946, were developed for the treatment of cancer. 31 – 33 In 2014, two more IRE1 inhibitors were manufactured, with B-I09 showing significant therapeutic efficacy in a variety of hematologic tumors and KIRA6 playing a role in the treatment of metabolic diseases. 34 , 35 In 2015, AMG-44 was developed as a highly potent and selective PERK inhibitor that targets and alleviates ER stress-associated pathological processes by sensing the UPR and inhibiting its activity, providing novel tool compounds for the treatment of diseases such as cancer. 36 In 2017, a major breakthrough was made in the treatment of type 1 diabetes by targeting ER stress; attenuating IRE1 reduces pancreatic β-apoptosis and reverses type 1 diabetes (T1D). The IRE1 inhibitor KIRA8 was also effective in reversing established diabetes by preserving the physiological function of β-cells. 37 In 2019, the IRE1-specific inhibitor MKC8866 strongly inhibited prostate cancer tumor growth and showed synergistic antitumor effects with current drugs. 38 In 2021, a novel pancreatic cancer therapeutic agent, YUM70, was developed with the primary function of inducing ER stress-mediated apoptosis in tumor cells by inhibiting GRP78. 39 In 2022, a breakthrough in tumor therapy was achieved when a novel tumor vaccine against ER stress began to be put into clinical trials as an active immunotherapy. 40 In 2023, Benson’s team discovered that the gut flora metabolite trimethylamine N-oxide (TMAO) exacerbates the progression of abdominal aortic aneurysm (AAA) through activation of the PERK/eIF2α/ATF4/CHOP axis, enhances apoptosis, and inhibits autophagy in vascular smooth muscle cells. Therefore, targeted inhibition of TMAO generation effectively attenuates ER stress and suppresses aneurysm pathology. 41 In 2024, Xu et al. revealed that the ER stress sensor IRE1 silences taxane-induced double-stranded RNA (dsRNA) through regulated IRE1-dependent decay (RIDD), thereby suppressing NLRP3 inflammasome-mediated pyroptosis in triple-negative breast cancer. Inhibition of IRE1 RNase activity restored dsRNA accumulation, triggering pyroptosis and the conversion of immunologically cold tumors into immunogenic tumors, increasing the efficacy of chemoimmunotherapy. 42 In summary, ER stress, a key biological process, is closely related to the occurrence and development of many diseases. By revealing the mechanism of ER stress and exploring its role in cancer, cardiovascular diseases, metabolic diseases, neurodegenerative diseases, and autoimmune diseases, researchers have provided new directions for future therapeutic strategies (Fig. 1 ). Fig. 1 Timeline of ER stress-related research. The timeline summarizes key findings and developments in ER stress-related research, demonstrating the ongoing progress and innovation in this field. The key protein involved in ER stress, BiP/GRP78, was discovered for the first time in 1977. The UPR can subsequently help cells adapt to this stress to some extent, but prolonged ER stress can also lead to cell death. Three key proteins involved in the UPR were successively discovered in mammalian cells from 1998--1999. Thus, ER stress has been shown to play an important role in various types of diseases. Drugs that target inhibitors of ER stress-related pathways were developed in 2006. In the following decade, an increasing number of ER stress-related pathway inhibitors, the most commonly used of which include B-I09, GSK2606414, ISRIB, and 4μ8C, were used in clinical therapy. Currently, ER stress pathway inhibitors are widely used, and novel tumor vaccines targeting them have been successfully developed Timeline of ER stress-related research. The timeline summarizes key findings and developments in ER stress-related research, demonstrating the ongoing progress and innovation in this field. The key protein involved in ER stress, BiP/GRP78, was discovered for the first time in 1977. The UPR can subsequently help cells adapt to this stress to some extent, but prolonged ER stress can also lead to cell death. Three key proteins involved in the UPR were successively discovered in mammalian cells from 1998--1999. Thus, ER stress has been shown to play an important role in various types of diseases. Drugs that target inhibitors of ER stress-related pathways were developed in 2006. In the following decade, an increasing number of ER stress-related pathway inhibitors, the most commonly used of which include B-I09, GSK2606414, ISRIB, and 4μ8C, were used in clinical therapy. Currently, ER stress pathway inhibitors are widely used, and novel tumor vaccines targeting them have been successfully developed

ER stress is a cellular response that occurs when ER function is compromised or when the ER load exceeds normal capacity and has emerged as a key factor in the pathogenesis of numerous diseases. The ER is vital for protein synthesis and folding, calcium ion transport, and energy metabolism. However, various stimuli, such as nutrient deprivation, oxidative stress, and pathological conditions, can disrupt ER function, resulting in the accumulation of misfolded proteins. This triggers the unfolded protein response (UPR), a complex signaling network that aims to restore ER homeostasis. Understanding the underlying causes of ER stress, its downstream signaling factors, and regulatory pathways is essential for elucidating its role in various diseases. This knowledge provides insights into disease mechanisms and offers potential therapeutic targets for intervention. The following sections explore these aspects in detail, shedding light on the multifaceted role of ER stress in health and disease. As an adaptive cellular response to ER stress, the UPR is activated to restore homeostasis at the cellular level when impaired ER function results in the accumulation of unfolded or misfolded proteins. 43 In 1977, researchers discovered that excessive glucose consumption led to cessation or significant inhibition of protein synthesis, a phenomenon not fully understood until the UPR was recognized in 1992. 14 , 15 The mammalian UPR pathway is composed of three central signaling cascades (inositol-requiring protein 1 (IRE1), activating transcription factor 6 (ATF6), and protein kinase R-like ER kinase (PERK)) activated by transmembrane sensors in the ER, which coordinate responses to the harmful accumulation of unfolded or misfolded proteins. 44 BiP/GRP78 acts as a molecular chaperone protein within the ER that binds and releases the three UPR sensors on the ER membrane. 45 Under normal conditions, BiP binds to these sensors and keeps them inactive. Nevertheless, when there is an increase in unfolded proteins within the ER, BiP dissociates from some of the binding sites in these sensors, thereby activating them and initiating the UPR response (Fig. 2 ). Fig. 2 Causes of the ER stress response and the triggering process of the UPR. The ER consists of a series of lamellar vesicles and tubular lumens, forming a continuous reticular system that links the nucleus, cytoplasm, and cell membrane. Many endogenous and exogenous cellular factors contribute to ER dysfunction in cancer cells, including abnormal protein synthesis, calcium imbalance, genetic alterations, dysfunction of mitochondria, lack of oxygen, nutrient availability, acidic pH, oxidative stress, and therapy status. These factors contribute to the ER stress response. As an adaptive cellular response to ER stress, the UPR is activated to restore homeostasis at the cellular level when impaired ER function results in the accumulation of unfolded or misfolded proteins. Three of the most classical genes in the UPR are IRE1, ATF6, and PERK. When GRP78, also known as BiP, releases the three UPR sensors in the ER membrane, they act synergistically through different mechanisms in response to the accumulation of unfolded proteins. IRE1, a receptor kinase on the ER membrane, is activated when unfolded proteins accumulate in the ER. Upon UPR activation, IRE1 dimerizes and autophosphorylates, activating its RNase domain. This leads to the excision of a 26-nucleotide fragment from XBP1 mRNA, producing spliced XBP1 mRNA that encodes the active XBP1 protein. Spliced XBP1 then activates genes that aid in restoring ER function. Moreover, IRE1 RNase modulates RIDD to selectively degrade ER-associated mRNAs, affecting protein folding. ATF6 is translocated from the ER membrane to the Golgi during the accumulation of unfolded proteins, where it is cleaved to form small fragments of active ATF6 called ATF6αp50. This small fragment can enter the nucleus and facilitate the transcription of genes related to protein folding, such as those that enhance the folding function of molecular chaperones and the ER, helping to restore normal protein function. PERK, a kinase located on the ER membrane, inhibits global protein synthesis by phosphorylating eIF2α upon activation. This process reduces overall translation, allowing the ER more time and resources to address misfolded proteins while also preferentially translating specific protective mRNAs, such as ATF4, to alleviate the ER burden. In addition, during ROS-mediated ER stress, PERK contributes to apoptosis by maintaining proapoptotic CHOP levels when ER stress cannot be relieved Causes of the ER stress response and the triggering process of the UPR. The ER consists of a series of lamellar vesicles and tubular lumens, forming a continuous reticular system that links the nucleus, cytoplasm, and cell membrane. Many endogenous and exogenous cellular factors contribute to ER dysfunction in cancer cells, including abnormal protein synthesis, calcium imbalance, genetic alterations, dysfunction of mitochondria, lack of oxygen, nutrient availability, acidic pH, oxidative stress, and therapy status. These factors contribute to the ER stress response. As an adaptive cellular response to ER stress, the UPR is activated to restore homeostasis at the cellular level when impaired ER function results in the accumulation of unfolded or misfolded proteins. Three of the most classical genes in the UPR are IRE1, ATF6, and PERK. When GRP78, also known as BiP, releases the three UPR sensors in the ER membrane, they act synergistically through different mechanisms in response to the accumulation of unfolded proteins. IRE1, a receptor kinase on the ER membrane, is activated when unfolded proteins accumulate in the ER. Upon UPR activation, IRE1 dimerizes and autophosphorylates, activating its RNase domain. This leads to the excision of a 26-nucleotide fragment from XBP1 mRNA, producing spliced XBP1 mRNA that encodes the active XBP1 protein. Spliced XBP1 then activates genes that aid in restoring ER function. Moreover, IRE1 RNase modulates RIDD to selectively degrade ER-associated mRNAs, affecting protein folding. ATF6 is translocated from the ER membrane to the Golgi during the accumulation of unfolded proteins, where it is cleaved to form small fragments of active ATF6 called ATF6αp50. This small fragment can enter the nucleus and facilitate the transcription of genes related to protein folding, such as those that enhance the folding function of molecular chaperones and the ER, helping to restore normal protein function. PERK, a kinase located on the ER membrane, inhibits global protein synthesis by phosphorylating eIF2α upon activation. This process reduces overall translation, allowing the ER more time and resources to address misfolded proteins while also preferentially translating specific protective mRNAs, such as ATF4, to alleviate the ER burden. In addition, during ROS-mediated ER stress, PERK contributes to apoptosis by maintaining proapoptotic CHOP levels when ER stress cannot be relieved IRE1, a crucial upstream transmembrane protein for the ER stress response, was identified in mammals in 1993. 46 Upon UPR activation, IRE1 dimerizes and undergoes autophosphorylation, which activates its RNase structural domain through conformational changes. 47 The excision of a 26-nucleotide fragment from X-box binding protein 1 (XBP1) mRNA on the cell membrane results in spliced XBP1 mRNA that encodes the active XBP1 protein. 48 XBP1 activates several genes associated with protein folding, ER-associated degradation (ERAD), and lipid synthesis, thereby helping cells restore ER function. 49 Under severe ER stress, sustained activation of IRE1 enhances the XBP1-dependent expression of the classical UPR gene, which may promote cell injury. 50 Recent studies have shown that IRE1 RNase modulates RIDD to selectively degrade ER-associated mRNAs, affecting the protein-folding load, cellular metabolism, inflammation, and inflammasome signaling. 51 Moreover, prolonged activation of IRE1 can promote cell death by activating apoptotic pathways such as the c-Jun N-terminal kinase (JNK) pathway. 52 ATF6, which was first isolated in 1998 via a yeast one-hybrid screen, is considered a putative ER stress-binding protein. 17 Under non-ER stress conditions, ATF6 and BiP form a stable complex in the ER, with BiP inhibiting glutaminase (GLS). Upon activation, the N-terminal fragment of ATF6 is translocated to the nucleus, where it promotes the transcription of genes with ER stress response elements and those targeted by the UPR. 53 ATF6 regulates the expression of a series of key genes in the ER homeostasis network, which encode proteins that contribute to cellular stress resistance and thus protect cells from damage. 54 Moreover, given the overlapping functions of IRE1 and ATF6α, some ATF6α targets are also regulated by XBP1, although this influence is less significant than that of IRE1 in ER stress. 55 XBP1 and ATF6p50 induce changes in the structure and function of the ER, contributing to the phenotype of professional secretory cells by expanding the surface area of the ER to support cellular functions during ER stress. 56 PERK was identified in 1999 and features a luminal structural domain akin to that of IRE1, which senses ER stress. 57 The signature role of PERK is to phosphorylate eIF2α and inhibit protein synthesis, thereby coregulating the integrated cellular stress response. 55 PERK inhibits global translation by phosphorylating the translation factor eIF2α, which preferentially translates certain protective mRNAs (e.g., ATF4) to reduce the ER burden. Recent findings indicate that ER whorl formation, an ER stress effector mechanism, depends on PERK kinase activity and the coat protein complex II (COPII) mechanism, aiding in ER stress-induced translational repression. 58 By inhibiting protein synthesis, PERK reduces the entry of new proteins into the ER, thereby relieving the burden on the ER. In addition, PERK activates other signaling pathways, such as antioxidative stress and apoptosis regulation, to help cells adapt to stressful environments. During reactive oxygen species (ROS)-mediated ER stress, when ER stress cannot be reversed, PERK contributes to apoptosis by maintaining proapoptotic CHOP levels and facilitating the propagation of ROS signals between the ER and mitochondria. 59 The ER contains many chaperone proteins, glycosylases, and oxidoreductases, creating an optimal environment for folding nascent peptide chains. 60 Factors such as abnormal protein synthesis, calcium imbalance, genetic and epigenetic factors, mitochondrial dysfunction, a lack of oxygen, reduced nutrient availability, acidic pH, oxidative stress, and tumor therapy collectively contribute to the ER stress response (Fig. 2 ). Abnormal protein synthesis is the primary cause of ER stress. Typically, newly synthesized proteins undergo complex folding to ensure their correct three-dimensional conformation. 61 When molecular chaperone proteins in the ER, such as BiP/GRP78, are damaged or do not function, the cell fails to correctly fold proteins. 57 This leads to missynthesis of proteins in the ER and subsequent initiation of the ER stress state to mitigate ER damage. In addition, blockage of protein degradation pathways can also lead to excessive protein accumulation and activate ER stress, the most common of which is the ubiquitin‒proteasome pathway. 62 The epithelial‒mesenchymal transition (EMT) process involves the synthesis and secretion of large amounts of extracellular matrix proteins, which affect the protein secretion rate, leading to protein accumulation and triggering ER stress responses. 63 Since the ER cannot be generated de novo, proliferating cancer cells necessitate rapid ER expansion or division to distribute to daughter cells. These findings suggest that the protein synthesis rate is a crucial driver of ER stress and tumorigenicity in vivo. 64 The ER is an important calcium ion reservoir in the cell that regulates calcium ion uptake, storage, and signaling. 65 Hence, disturbances in calcium ion homeostasis are among the most common factors contributing to the development of ER stress. 66 Elevated levels of calcium ions in the cytoplasm under pathological conditions induce the activation of proteases, lipases, and nucleases. 67 When calcium adenosine triphosphatase (ATPase), such as Sarco/(endo) plasmic reticulum Ca2+ ATPase, is pumped into the ER, it leads to abnormal loss or release of calcium ions. 68 Leakage of calcium ions directly affects the calcium concentration within the ER, causing the internal environment to become unstable and affecting the normal folding of proteins. When the ER senses this instability, the ER stress response is initiated. Collins et al. reported that deletion of sensor substrate interaction molecule 1 (STIM1), which stores calcium ions, leads to age-dependent ER stress, altered mitochondrial morphology, and dilated cardiomyopathy in mice. 69 During calcium ion transfer, impaired function, overactivation, or aberrant expression of channels between the ER and the cytoplasm (inositol 1,4,5-trisphosphate receptor) leads to uncontrolled opening or closing of the channels, thereby disrupting ER calcium ion homeostasis. 70 Importantly, calcium-binding proteins play a critical role in ensuring proper protein folding. Calnexin is a calcium-binding protein in the ER membrane that interacts with specific glycosylated proteins and promotes proper folding. 71 Calreticulin (CALR), another common calcium-binding protein, is extensively involved in biological processes such as ER calcium homeostasis and protein processing. It is involved in recognizing and repairing incompletely folded or misfolded proteins together with related molecular chaperones such as GRP78. 72 If CALR malfunctions, this process may be affected, causing misfolded proteins to fail to be repaired or degraded in time, which in turn causes ER stress. 73 Moreover, calcium ions may leak from the ER due to mutations, changes in the extracellular environment, or exposure to drugs or toxins, disrupting homeostasis and initiating ER stress. 74 Unfortunately, no studies have clarified the quantitative relationship between calcium signaling and ER stress, which requires further exploration. A variety of genetic and epigenetic factors influence the occurrence of ER stress. Genetic factors are characteristics and mechanisms directly determined by genes, and they influence the occurrence of ER stress through gene expression and regulation. Genetic defects in ER proteins promote the formation of misfolded proteins, inducing ER stress, which leads to disease. Functional defects in molecular chaperones or folding enzymes directly impair the protein-folding capacity of the ER, leading to the accumulation of unfolded proteins. Mutations in the folding enzyme PARK7 lead to mitochondrial dysfunction, affecting ER calcium homeostasis through mitochondria‒ER contact sites (MAMs) and leading to persistent activation of ER stress. 75 In addition, aberrant proteins produced by gene mutations may fail to pass through the ER quality control (ERQC) system and persistently activate ER stress. Lee et al. demonstrated that mutations in ChEL impaired thyroglobulin folding, which prevented thyroglobulin from leaving the ER and induced ER stress. 76 In tumor studies, malignant transformation requires a multistage reaction and the accumulation of genetic mutations that decouple proliferative capacity from extracellular regulation and growth factor-mediated regulation. 77 Specifically, the loss of tumor suppressors and the overexpression of oncogenes can significantly increase the rate of protein synthesis, meeting the heightened metabolic demands of tumorigenesis. 78 Oncogenic transformation dramatically increases the rate of protein synthesis, leading to ER stress, and the deletion of tumor suppressors such as p53 and phosphatase and tensin homolog (PTEN) is a major driver. 79 Loss of the tumor suppressor complex proteins tuberous sclerosis complex 1 (TSC1) and TSC2 has also been shown to activate the UPR in a cell-autonomous manner. 80 In addition, oncogenic BRAF-mediated p38 activation in melanoma stimulates the IRE1/apoptosis signal-regulating kinase 1 (ASK1)/JNK and TRB3 pathways, whose overexpression can induce a chronic ER stress state. 81 DNA methylation is an important epigenetic mechanism that regulates gene expression. 82 Abnormal DNA methylation patterns may lead to the downregulation of gene expression associated with ER function, which in turn affects the folding ability of the ER. 83 Histone modifications also regulate gene expression associated with ER stress. 84 The altered modification status of histones may affect the structure of chromatin and thus the transcription of ER stress-related genes. 85 In addition, epigenetic factors can interact with environmental factors to further exacerbate ER stress. For example, environmental factors such as diet, toxin exposure, and infections may alter the ER stress status by influencing epigenetic modifications such as DNA methylation and histone modifications. 86 In summary, genetic and epigenetic factors not only determine the ability of cells to respond to ER stress but also play important roles in the cellular response to environmental stress. Mitochondria are the energy factories of cells and are responsible for ATP production. 87 It plays an important role in the regulation of apoptosis, calcium ion homeostasis, and oxidative stress, and interacts with the ER through signaling pathways and substance exchange. 88 Numerous studies have shown that mitochondrial dysfunction can significantly increase the risk of ER stress in several ways. First, mitochondrial dysfunction directly reduces ATP production, an important energy source for the ER to maintain normal function. 89 Insufficient energy leads to impaired protein-folding processes in the ER, contributing to the accumulation of unfolded proteins. Second, the overproduction of ROS in mitochondria directly damages the ER membrane. 90 In addition, ROS affect folding enzymes and chaperone proteins (e.g., BiP) in the ER, thereby interfering with the normal folding process of proteins and leading to the accumulation of unfolded proteins, which triggers the ER stress response. 59 Third, when calcium ion release and storage are abnormal during mitochondrial dysfunction, resulting in altered calcium ion concentrations in the ER, excess calcium ions can cause ER stress. 91 This is because the ER also depends on normal levels of calcium ions to maintain its function, as mentioned in the previous sections. Finally, decreased mitochondrial function may also lead to changes in intracellular metabolites, and the inability to utilize these metabolic intermediates efficiently affects protein folding and modification within the ER, leading to the accumulation of unfolded or misfolded proteins. 92 If mitochondrial dysfunction and ER stress persist, cells may enter an apoptotic program, further affecting cell and tissue function. 93 In addition to genetic alterations in cancer cells that can contribute to ER stress, abnormal conditions in the tumor microenvironment (TME) can also lead to sustained activation of the UPR pathway. 50 The Warburg effect suggests that cancer cells favor aerobic glycolysis, but normal cells rely primarily on anaerobic glycolysis to produce ATP. 94 Owing to rapid cell division and abnormal angiogenesis, hypoxic features arise in the tumor, thus disturbing the balance of the ER. 95 Research indicates that hypoxia, which is prevalent in tumors, increases both the level and activity of hypoxia-inducible factor-1α (HIF-1α), thereby inducing ER stress that can lead to irreversible cellular damage. 96 Cellular energy is supplied by the metabolism of glucose and lipids. 97 If the supply of nutrients is insufficient, the metabolic activity of the cells is limited, resulting in an energy deficit that interferes with the normal functioning of the ER. 98 A study investigating the gene expression profile of melanoma cells revealed a significant increase in isocitrate dehydrogenase 1 (IDH1), which is essential for cellular metabolism and energy conversion, 99 in response to ER stress. Compared with the standard energy requirements of cells, an inadequate supply of nutrients characterizes metabolic stress, which can quickly destroy ER homeostasis. Nutrient deprivation, which notably reduces glucose flux through the hexosamine pathway, curtails the metabolic intermediates necessary for the hexosamine biosynthetic pathway (HBP), thereby allowing activated ER stress to dictate the fate of malignant cells. 100 Glucose restriction also impairs mitochondrial ATP production, and energy deficiency affects the ability to fold proteins in the ER. 101 Moreover, fatty acids are not only a source of energy but also a building block of cell membranes. 102 In nutritional deficiency, the supply of fatty acids is also affected, which in turn affects the membrane structure and function of the ER, leading to ER stress. 103 Studies have shown that ER stress is closely related to the pH of the intracellular environment. Changes in pH may lead to alterations in the permeability of cell membranes, causing changes in the exchange of ions and molecules inside and outside the cell, especially when acidosis conditions occur. 104 Cancer cells use aerobic glycolysis as a central metabolic pathway, producing lactate, which lowers the local extracellular pH. 105 After secretion, lactic acid destabilizes the HIF-1α protein and synergizes with hypoxia to robustly activate the ER stress response. 106 Recent studies have shown that lactate can also activate Caspase-12 to induce apoptosis and lung fibrosis in alveolar epithelial cells via the ATF4/CHOP axis during ER stress. 107 Sharma et al. verified that an acidic environment activates ER stress by detecting the splicing of XBP1 mRNA. 108 In addition, acidic pH activates ER stress-related pathways, leading to increased expression of IRE1, ATF6, and eIF2α. 109 IRE1 is activated by autophosphorylation of its intracellular kinase domain, leading to the dissociation of IRE1 from the dimer and the formation of the active form. 110 The acidic environment causes ATF6 to detach from the ER membrane, undergo Golgi processing, and be cleaved into the active transcription factor ATF6p50, which is subsequently translocated into the nucleus to initiate the transcription of a range of genes, including those involved in aspects of protein folding and lipid synthesis. 111 In addition, PERK under acidic stress activates the phosphorylation of eIF2α, which inhibits global protein synthesis and reduces the burden of new protein synthesis. 112 Oxidative stress is an imbalance between oxidation and antioxidant effects in the body, leading to the overproduction of oxidizing substances and dysfunction of the antioxidant defense system. 113 This state can cause inflammatory neutrophil infiltration, increased protease secretion, and the generation of oxidative intermediates. Furthermore, oxidative stress can initiate ER stress through various pathways. Products of oxidative stress have oxidative properties that can directly oxidize and damage protein structures within the cell. 114 Oxidatively damaged proteins usually lose their normal folded state, leading to aggregation and instability, accumulation in the ER, and triggering ER stress. 115 Notably, recent studies highlight the critical role of the Keap1/Nrf2 axis in bridging oxidative stress and ER homeostasis. For example, TRIM25, a ubiquitin E3 ligase induced during ER stress, promotes Nrf2 activation by ubiquitinating and degrading Keap1. This enhances antioxidant defenses (e.g., HO1 and NQO1), reduces ROS accumulation, and alleviates ER stress-induced protein misfolding. 116 Additionally, oxidative stress can precipitate ER stress by inhibiting protein-folding enzymes, impairing the function of molecular chaperones, or diminishing the efficiency of protein repair processes. 117 Under oxidative stress conditions, ROS and oxidative protein modifiers can directly or indirectly activate ER stress sensors, such as ATF6. The activation of these sensors triggers a cascade of ER stress signals, thereby inducing a series of adaptive responses. Jin et al. elucidated the dual role of ATF6 in ER stress and oxidative stress, which means that the hydroxylase produced by ATF6-induced oxidative stress can also act as an ER stress response element. 118 Radiotherapy induces ER stress, and the induction of ER stress responses may contribute to adaptive survival signaling in cancer cells. Since radiation-exposed cells exhibit increased UPR activity, several studies have shown that the knockdown of ER stress-related genes contributes to increased radiation-induced cell death. 119 During chemotherapy, various anticancer drugs induce robust ER stress responses, correct uncontrolled protein states, and determine the future of cells. Therapeutic regimens that rely on immune cell death (ICD) inducers, including cetuximab, anthracyclines, and oxaliplatin, 120 can trigger ER stress by depleting calcium ions within the ER, suggesting that genes associated with this mechanism could be drug targets and ultimately activate antitumor responses. 121 In addition, paclitaxel induces ER stress in breast cancer cells, which promotes the association of ring-finger protein 5 (RNF5), ubiquitination, and degradation of solute carrier transporter 1A5 (SLC1A5) and SLC38A2, and can promote anticancer drug efficacy. 122 Thus, depending on the setting and tumor type, the interplay between various anticancer drugs and ER stress signaling critically influences the endogenous anticancer immune response, markedly altering disease progression. 50 In addition, the ROS produced by the latest photodynamic therapy can also trigger protein misfolding, leading to ER stress. 123 For example, the fluorophore IR-34 can accurately trigger the ER stress response in tumor cells to stop cancer progression. Currently, novel nanomedicines have been developed to induce ER stress in tumor cells, and they exacerbate apoptosis by upregulating ER stress-associated proteins. In addition to the three classical pathways of the UPR, ER stress involves other downstream effectors for protein folding, transport, and degradation regulation, as well as many adaptive mechanisms for maintaining cellular homeostasis (Fig. 3 ). Fig. 3 Downstream effectors and multilevel regulation of ER stress. The goal of the UPR is to restore the normal function of the ER through several mechanisms: enhancement of protein folding and repair function, enhancement of protein degradation, and inhibition of protein synthesis. The cytoplasmic portion of IRE1 binds to TRAF2, which activates JNK and is involved in the regulation of apoptosis. IRE1 activation promotes the expression of the ERAD-related genes SEL1L and HRD1, which facilitate the degradation of unfolded or misfolded proteins via ERAD. Upon activation of ATF6, SEL1L also induces EDEM, which helps cells recognize and degrade unfolded or misfolded proteins. ATF6 promotes protein quality control mechanisms under ER stress by upregulating EDEM expression. In addition, TXNDC5 can be induced by ATF6, thereby increasing the efficiency of protein folding in the ER. PERK can regulate the expression of ERDJ4 by activating ATF4, which helps improve ER protein folding. In addition, the PERK signaling pathway upregulates Nrf2 via ATF4 and promotes antioxidant gene expression. PERK can also affect cell growth and autophagy through the mTOR signaling pathway. The activation of PERK inhibits mTOR, leading to alterations in cellular metabolism and the enhancement of autophagy processes, which can help remove damaged cellular components. Upon triggering of the UPR, the IRE1, ATF6, and PERK pathways are activated as downstream execution mechanisms, altering cellular features through different molecular and biochemical pathways. These features include proliferation, angiogenesis, metastasis, reactivation of dormant cells, cell death, cell metabolism, and therapeutic resistance Downstream effectors and multilevel regulation of ER stress. The goal of the UPR is to restore the normal function of the ER through several mechanisms: enhancement of protein folding and repair function, enhancement of protein degradation, and inhibition of protein synthesis. The cytoplasmic portion of IRE1 binds to TRAF2, which activates JNK and is involved in the regulation of apoptosis. IRE1 activation promotes the expression of the ERAD-related genes SEL1L and HRD1, which facilitate the degradation of unfolded or misfolded proteins via ERAD. Upon activation of ATF6, SEL1L also induces EDEM, which helps cells recognize and degrade unfolded or misfolded proteins. ATF6 promotes protein quality control mechanisms under ER stress by upregulating EDEM expression. In addition, TXNDC5 can be induced by ATF6, thereby increasing the efficiency of protein folding in the ER. PERK can regulate the expression of ERDJ4 by activating ATF4, which helps improve ER protein folding. In addition, the PERK signaling pathway upregulates Nrf2 via ATF4 and promotes antioxidant gene expression. PERK can also affect cell growth and autophagy through the mTOR signaling pathway. The activation of PERK inhibits mTOR, leading to alterations in cellular metabolism and the enhancement of autophagy processes, which can help remove damaged cellular components. Upon triggering of the UPR, the IRE1, ATF6, and PERK pathways are activated as downstream execution mechanisms, altering cellular features through different molecular and biochemical pathways. These features include proliferation, angiogenesis, metastasis, reactivation of dormant cells, cell death, cell metabolism, and therapeutic resistance IRE1, upon activation, promotes the expression of genes related to ERAD, including suppressor/enhancer of Lin-12-like (SEL1L) and 3-hydroxy-3-methylglutaryl reductase degradation (HRD1), which is a pathway responsible for recognizing and degrading unfolded or misfolded proteins in the ER. 124 For proteins that do not fold correctly, cells mark them for degradation via ERAD, preventing them from accumulating and causing cytotoxicity. 125 By degrading misfolded proteins, IRE1 helps maintain ER homeostasis. Furthermore, the cytoplasmic portion of IRE1 binds to TNF receptor-associated factor 2 (TRAF2), an articulatory protein that binds plasma membrane receptors to activate JNK. 126 Sustained activation of IRE1 can induce JNK through the TRAF2 pathway, which is involved in regulating cell survival and apoptosis, especially in the presence of more severe ER stress. On this basis, IRE1 can also promote activator protein 1 (AP1) activation through JNK. 127 AP1 is a transcription factor complex involved in regulating the expression of various genes. It plays an important role in mainly cell survival and apoptosis, which has been demonstrated in human aortic endothelial cells. 128 IRE1 also promotes the expression of interleukin-6 (IL-6), which acts as a proinflammatory cytokine that is associated with a variety of diseases (e.g., cancer and diabetes) by activating the JNK pathway to potentiate inflammatory responses. 129 Under severe ER stress, IRE1 induces the expression of FAS (CD95) and other proapoptotic factors and enhances apoptotic signaling. 130 The activation of ATF6 induces ER degradation-enhancing α-mannosidase-like protein (EDEM) in the ERAD pathway to help recognize and degrade unfolded or misfolded proteins. 131 ATF6 promotes protein quality control mechanisms under ER stress by upregulating EDEM expression. 132 Gan et al. reported that EDEM3 overexpression attenuated adipocyte ER stress, improved adipocyte endocrine function, and restored plasma adiponectin levels. 133 Another ERAD-related gene, SEL1L, is involved in recognizing and removing misfolded proteins. Together with HRD1, it forms a complex responsible for delivering incorrectly folded proteins to the proteasome for degradation. 134 ATF6 enhances the ERAD pathway by activating SEL1L, ensuring that misfolded proteins are rapidly recognized and degraded, preventing these proteins from accumulating and triggering toxicity. 135 Homocysteine-induced ER protein (HERP), which is also involved in the ERAD pathway, can accelerate the degradation of misfolded proteins during ER stress via ATF6. 136 Protein disulfide isomerase (PDI) is an important ER enzyme responsible for forming and rearranging disulfide bonds in proteins to ensure correct protein folding. 137 Thioredoxin domain containing 5 (TXNDC5), a PDI, was recently shown to be induced by ATF6, increasing the efficiency of protein folding in the ER and potentially ameliorating liver fibrosis. 138 In addition, ATF6 can regulate cell survival in response to cellular stress and inflammation by affecting the expression of CCAAT/enhancer-binding protein (C/EBP). 139 PERK can regulate the expression of ER dnaJ 4 (ERDJ4) through ATF4, which acts as a chaperone protein to help improve the protein-folding ability of the ER and alleviate ER stress. 140 Growth arrest and DNA damage-inducible protein 34 (GADD34), one of the target genes of ATF4, can restore protein synthesis by promoting eIF2α dephosphorylation. 141 NADPH oxidase 4 (NOX4) plays a role in the cellular response to oxidative stress, and the PERK signaling pathway can regulate NOX4 expression to activate cellular autophagy events. 142 The PERK signaling pathway promotes antioxidant gene expression by upregulating nuclear factor erythroid 2-related factor 2 (Nrf2) through ATF4. 143 Mohamed et al. reported that tumor myeloid-derived suppressor cells (MDSCs) lacking PERK exhibited disrupted Nrf2-driven antioxidant capacity and impaired mitochondrial respiratory homeostasis. 144 Therefore, Nrf2 activation protects cells from oxidative stress-induced damage, thereby preserving cell survival. In addition, C/EBPβ is activated in response to ER stress through the PERK pathway and is involved in regulating cell growth and survival. The activation of C/EBPβ can influence the cell cycle and apoptosis and has recently been shown to be effective in blocking MDSC activation in tumors, leading to TME remodeling and tumor regression. 145 Caspases are also key enzymes involved in apoptosis, and activation of the PERK pathway can direct the activation of executing enzymes, such as caspase-3, to trigger apoptosis. 146 PERK can also affect cell growth and autophagy by regulating the mechanistic target of the rapamycin kinase (mTOR) signaling pathway. 147 Under ER stress, the activation of PERK inhibits mTOR, leading to alterations in cellular metabolism and the enhancement of autophagy processes, which can help remove damaged cellular components and play a protective role in response to ER stress. In summary, downstream regulators of ER stress help cells cope with ER dysfunction by participating in protein folding, transport, and degradation, as well as cellular homeostatic and adaptive mechanisms. These mechanisms are essential for maintaining cellular health and can effectively prevent cellular damage and diseases caused by abnormal protein folding. Once the UPR is triggered, the IRE1, ATF6, and PERK pathways are activated as downstream executive mechanisms, altering cellular features through different molecular and biochemical pathways. 148 These features include proliferation, angiogenesis, metastasis, reactivation of dormant cells, cell death, cell metabolism, and treatment resistance (Fig. 3 ). Since tumor cells typically reside in a highly metabolically active and fast-growing environment, an increased ER burden can trigger ER stress. Specifically, ER stress promotes tumor cell proliferation when signaling molecules in the ER stress pathway, such as XBP1, are activated, along with the expression of antioxidant response genes. 149 Additionally, a study demonstrated that persulfate-based degradation of perfluorooctanoic acid (PFOA) induced ER stress, activating the ROS-dependent ERK signaling pathway. 150 Low concentrations of PFOA induced ER stress and activated the PERK/eIF2α pathway in the UPR while significantly increasing ROS production. ROS further regulates kinase phosphorylation through the activation of extracellular signals, thereby promoting trophoblast cell proliferation. Furthermore, Blazanin et al. reported that Ras carcinogen-induced proliferation is directly related to ER stress, with the IRE1/XBP1 pathway playing a dominant role. 151 Consequently, these mechanisms enable tumor cells to adapt to stress, survive, and proliferate. In atherosclerosis, ER stress can contribute to the proliferation of vascular smooth muscle cells, leading to intimal thickening. 152 Zhou et al. reported that this effect is due mainly to increased CHOP expression, which in turn promotes cell proliferation by downregulating KLF4. Angiogenesis, which is crucial for tumor growth, relies on intracellular ER stress signals to secure oxygen and nutrients, facilitating growth and waste removal. 50 It has been shown that activating IRE1 and PERK in tumor cells induces the expression of vascular endothelial growth factor (VEGF). Specifically, in glioblastoma, inhibiting IRE1 leads to the downregulation of various VEGFs, adversely affecting angiogenesis. 153 Insufficient expression of IRE1 has been linked to reduced angiogenesis and decreased growth rates, highlighting its role as a key regulator of tumor neovascularization and aggressiveness. Moreover, ER stress further promoted VEGF expression by activating the HIF-1α pathway. 154 Under a hypoxic environment, HIF-1α can promote neovascularization through the VEGF pathway, and ER stress enhances this process through IRE1, PERK, and other pathways. 155 The PERK/ATF4 arm of the UPR has been identified as a mediator of the angiogenic switch, with the inhibition of UPR signaling significantly reducing tumor growth and vascular density, suggesting a potential target for cancer therapy. 156 Unlike the traditional ER stress response, VEGF activates the UPR through phospholipase C‒gamma (PLCγ)-mediated interaction with the mTORC1 complex, where a lack of ATF6 or eIF2α significantly reduces VEGF-induced angiogenesis. 157 The UPR supports multiple stages of metastasis, especially through PERK’s role in upregulating lysosome-associated membrane protein 3 (LAMP3), which is essential for hypoxia-driven nodal metastasis, thereby amplifying metastatic traits. 158 Additionally, RNA editing proteins trigger ER stress in colorectal cancer metastasis, enabling ATF6, XBP1, and ATF4 to move to the nucleus, activate metastasis-related genes, and enhance tumor cell invasion. 159 In osteosarcoma cells, increased ATF6α cleavage and activity lead to increased BiP expression and an increased likelihood of metastasis. 160 Deletion of tumor suppressor candidate 3 (TUSC3) through miR-224/-520c enhances the ATF6α-dependent UPR and inhibits the p53-NM23H1/2 pathway, increasing the metastatic potential of lung cancer. 161 Elevated heat shock protein 47 (HSP47) levels enhance actin filament contractility via the interaction of IRE1 with nonmyosin, promoting metastasis in aggressive breast cancer cells. 162 Dormant cells, which remain hidden and asymptomatic for extended periods, can reactivate, significantly contributing to cancer recurrence after treatment and potentially serving as a stage for metastasis. 163 For example, cancer stem cells in tumors are often dormant and can enter a proliferative state through the reactivation of ER stress signals to drive tumor growth. 164 Studies have demonstrated that the activation of various UPR pathways, such as increased phosphorylation of PERK/eIF2α, supports dormant tumor cell survival. Inhibiting PERK signaling can reverse this phenotype, significantly improving treatment outcomes. 165 The three UPR pathways collectively contribute to the angiogenic, metastatic, and dormant properties of tumor cells, each to varying degrees. Cells initiate apoptosis if the ER stress response fails to maintain proteostasis, leading to persistent imbalance. 3 The apoptotic program is often attributed to dysregulated calcium homeostasis, with the ER playing a crucial role in calcium ion storage. 166 Following ER stress, stimulation from various signals, including PERK and eIF2α, opens inositol 1,4,5-triphosphate receptor (IP3R) channels in the ER membrane, causing a substantial release of calcium ions. 167 Elevated levels of calcium ions activate calpain by binding to calcium-dependent proteases. This enzyme cleaves various proteins, including B-cell lymphoma-extralarge (Bcl-xL), shifting it from being antiapoptotic to being proapoptotic. 168 Furthermore, activated calpain can move to the ER, where it cleaves and activates caspase-12 at multiple sites, playing a critical role in apoptosis. Additionally, triggering pharmacological ER stress selectively removes live sequestration of damaged ER and may help cells maintain a new steady-state level of ER abundance. 169 Chlorpromazine (CPZ), a novel pharmacological approach for treating glioblastoma, targets the ER and thus affects the UPR. This perturbation leads to a solid autophagic response that hinders the malignant features of glioblastoma. 170 ER stress exerts a direct antitumor effect on human colon cancer as an upstream regulator of lentinan (SLNT, with significant tumor growth inhibition), which increases the Ca2+ concentration, autophagy, and apoptosis. 171 In a recent study, high concentrations of PFOA resulted in ER stress overload that exceeded the compensatory capacity of the UPR, triggered sustained PERK/eIF2α activation, and upregulated the expression of the proapoptotic transcription factors ATF4 and CHOP. In contrast to low concentrations of PFOA, which promote cell proliferation, high concentrations of PFOA induce CHOP, thereby inhibiting the expression of the antiapoptotic protein BCL-2 and activating the apoptotic pathway. 150 At the onset of ER stress, the activation of signaling pathways inhibits both glucose uptake and glycolytic processes. 172 Specifically, IRE1 activation inhibits translation and reduces glucose transporter type 4 (GLUT4) expression, decreasing glucose uptake and utilization. 173 In addition, activated PERK inhibits glucose uptake and utilization of external glucose by influencing the expression and activity of several key enzymes in the glycolytic pathway, decreasing the rate of fructose phosphate metabolism and thus inhibiting glucose metabolism. 174 ER stress-induced Ca2+ imbalance and UPR activation impair glucose metabolism, thereby promoting tumor progression. 175 ER stress also causes a decrease in the ability of the liver to respond to insulin by modulating the activity of enzymes in the liver associated with gluconeogenesis and glycogen synthesis. 176 Moreover, ER stress leads to impaired pancreatic β-cell function, affecting insulin synthesis and secretion, which in turn may trigger insulin resistance and diabetes. 177 In addition, the activation of ER stress affects lipid metabolism. ER stress inhibits adipocyte differentiation, such as by inhibiting beige adipogenesis through the PERK signaling pathway, which exacerbates metabolic dysfunction. Park et al. reported that estrogen can alleviate ER stress and restore the differentiation ability of adipose precursor cells through the NAMPT-NAD+ axis, providing a new target for the treatment of metabolic diseases such as obesity. 178 The PERK pathway in the UPR can promote SREBP processing and nuclear translocation by phosphorylating EIF2α, leading to INSIG1 degradation, which increases the expression of lipid synthesis-related genes. Sustained activation of SREBP1c promotes hepatic lipogenesis, leading to excessive cholesterol accumulation. 179 In addition, ER stress regulates INSIG stability through GP78, which affects SREBP activity and cholesterol synthesis. GP78 deficiency leads to SREBP1 hyperactivation and accelerates age-related metabolic disorders. 180 Lipid synthesis and ER stress are bidirectionally regulated. SREBP activation relieves short-term stress, but long-term SREBP activation increases the burden on the ER, resulting in a vicious cycle. 181 ER stress also inhibits the expression and activity of enzymes in the lipid synthesis pathway, leading to a decrease in intracellular triglyceride synthesis, which in turn leads to disturbed lipid metabolism. 182 ER stress sometimes contributes to lipid metabolism, and its activation enhances lipid degradation pathways, such as autophagy and lipoprotein metabolic pathways, which promote lipolytic metabolism. 183 Intervention with stearoyl coenzyme A desaturase inhibitors can effectively block tumor spread by altering lipid homeostasis and triggering ER stress. 184 In the regulation of energy metabolism, ER stress inhibits mitochondrial function and oxidative phosphorylation processes, thereby reducing intracellular ATP production, which is achieved mainly by regulating the signaling pathways of two key energy sensors, AMP-activated protein kinase (AMPK) and mammalian target of rapamycin complex 1 (mTORC1). Inhibition of mTORC1 signaling affects tumor growth in patients with xenograft hepatocellular carcinoma. Radiotherapy, a primary strategy for cancer treatment, sensitizes cells to stimuli, including ER stress. 185 On the one hand, ER stress can attenuate radiation-induced cytotoxic effects, leading to radioresistance. Sestrin2 normally aids in cancer therapy, but radiotherapy upregulates Sestrin2, mitigating oxidative and ER stress and thereby resisting treatment. 186 On the other hand, ER stress has also been reported to reduce radioresistance in a study of lung cancer. Baek et al. demonstrated that the interaction of procollagen-lysine, 2-oxoglutarate 5-dioxygenase 3 (PLOD3) with protein kinase C via IRE1 activates caspase-2,4-dependent apoptosis to reduce radioresistance in an ER stress-mediated manner. 187 The emergence of chemotherapeutic resistance, often linked to high mortality rates, highlights the critical roles of autophagy and apoptosis. Specific activation of one or more UPR pathways leads to different intensities and final targets of ER stress responses, which induce different chemoresistance mechanisms: enhancement or attenuation. A study on lung adenocarcinoma (LUAD) cells revealed that increasing cisplatin concentrations promote the ER stress-induced transition of the XBP1 3′UTR, reducing chemoresistance and enhancing therapeutic efficacy. 188 Wong et al. reported that stearoyl-CoA desaturase 1 (SCD1) promotes the formation of lipid droplets, which attenuates chemotherapy-induced ER stress. Therefore, pharmacological inhibition of SCD1 can increase the expression levels of eIF2α, ATF4, and CHOP to attenuate chemoresistance, an approach that has been clinically demonstrated. 189 Tunicamycin significantly increased chemotherapy-induced death in gastric cancer cells by inducing ER stress, primarily through the upregulation of PERK, IRE1, and XBP1. 190 Moreover, ER stress has the negative effect of enhancing chemoresistance during the treatment of some cancers. ER stress-induced silencing of PHLPP made cancer cells resistant to chemotherapeutic drugs in a study by Guo et al. 191 The knockdown of PHLPP can increase the expression of autophagy-related genes downstream of the eIF2α/ATF4 signaling pathway, one of the important pathways in the UPR, which can promote chemoresistance in colon cancer. A recent study revealed that high expression of LIM domain kinase 1 (LIMK1) in colorectal cancer cells promotes eIF2α phosphorylation, which induces ER stress and increases resistance to 5-fluorouracil (5-FU). 192 The mechanism underlying 5-FU chemoresistance involves LIMK1 interaction with eIF2α, which modulates the PERK/eIF2α/ATF4 axis to reduce 5-FU-induced apoptosis in tumor cells. In conclusion, ER stress-associated genes could be potential targets for circumventing chemoresistance.

ER stress is thought to be an adaptive mechanism that maintains ER homeostasis by increasing protein-folding capacity and degrading misfolded proteins. The dual role of ER stress has been reported in detail; it promotes cell survival through the UPR at the early stage and triggers apoptosis under prolonged stress. 499 Under transient ER stress, the UPR is activated through three major sensors and works synergistically to reduce stress. Sustained ER stress overwhelms adaptive mechanisms and shifts the UPR toward apoptosis. Chen et al. reported that Cab45S can inhibit the IRE1-JNK pathway by stabilizing BiP/GRP78, which plays an important role in the bidirectional regulation of ER stress and provides a key node for balancing cell survival and apoptosis. 500 Research has identified persistent ER stress as a new hallmark of disease progression. Genetic variants, hypoxia, metabolic abnormalities, and therapeutic agents can lead to ER stress, disrupting protein-folding homeostasis in normal tissue cells. This uncontrolled ER stress response promotes disease progression, such as the proliferation and metastasis of malignant cells, and increases their survival and adaptability. On the basis of these findings, therapeutic options targeting the three classical downstream pathways of the UPR and related proteins are becoming a hot topic in the fight against tumors, cardiovascular diseases, neurodegenerative diseases, metabolic diseases, and autoimmune diseases. In particular, the popularity of novel therapeutic technologies, such as cancer vaccines, has recently accelerated the development of drugs targeting the UPR signaling pathway. Successful drug utilization involves multiple levels of complexity. Three major pathways of the UPR coordinate cellular stress responses, in which complex cross-regulatory and feedback mechanisms exist. The UPR constitutes a complex regulatory network involving oxidative stress, autophagy, and apoptosis. The diversity of interactions and regulatory mechanisms of these pathways increases the difficulty of drug development. IRE1 activation promotes adaptive responses through XBP1 splicing, but its overactivation may induce apoptosis through the JNK pathway 52 ; PERK selectively activates ATF4 to increase antioxidant capacity while inhibiting global translation, but sustained activation triggers cell death via CHOP. 59 This duality requires that drugs must precisely modulate target activity within a specific threshold or that they may switch from therapeutic to toxic. This makes drug design highly precise and difficult to generalize, increasing the difficulty of drug development. In addition, significant differences between animal models and the clinic are also a problem. TUDCA improved insulin resistance in animal models, but the results of clinical trials are not significant, and improvements are still needed. 480 We fully discuss the differences in the triggering mechanisms and modes of action of ER stress in a wide range of diseases, including cancer, cardiovascular disease, neurodegenerative disease, metabolic disease, and autoimmune disease. This also suggests the need to develop highly specific targeted drugs to improve personalized therapeutic capabilities. Despite their various advantages, their safety remains to be further demonstrated, and many mechanisms remain to be explored (Fig. 7 ). Fig. 7 Therapeutic challenges and emerging strategies. This figure highlights unresolved mechanisms and translational barriers in the targeting of ER stress for therapeutic intervention. Major challenges include the lack of clarity in the characterization of ATF6 signaling. ATF6 signaling in immune cells and its spatial regulation within the TME remain poorly characterized. There is a lack of mechanistic insights into ATF6-mediated crosstalk between ER stress and immune evasion. Current research is limited by overreliance on single-disease models. Predominant reliance on isolated disease models fails to recapitulate ER stress dynamics in comorbid conditions. Inadequate representation of multiorgan interactions and systemic pathological cascades. The barriers to clinical translation remain significant. The complexity of ER stress-related signaling networks complicates target identification and validation. Scarcity of large-scale clinical trials and standardized biomarkers for assessing treatment efficacy. Differences between species give rise to safety concerns for clinical administration. Divergent drug responses between animal models and human physiology limit predictive accuracy. Potential off-target effects of ER stress modulation on normal cellular homeostasis require rigorous evaluation. Future strategies emphasize cross-disease integration through multiomics and systems biology. Precision therapeutics could leverage genomic/proteomic profiling for patient-specific UPR pathway modulation. Innovations such as nanogel-based drug carriers and ER stress-responsive vaccines may enhance spatiotemporal control and synergize with immunotherapy. Advanced models, including CRISPR-edited organoids, multidisease murine systems, and organ-on-chip platforms, aim to replicate human pathophysiology and tumor-immune interplay Therapeutic challenges and emerging strategies. This figure highlights unresolved mechanisms and translational barriers in the targeting of ER stress for therapeutic intervention. Major challenges include the lack of clarity in the characterization of ATF6 signaling. ATF6 signaling in immune cells and its spatial regulation within the TME remain poorly characterized. There is a lack of mechanistic insights into ATF6-mediated crosstalk between ER stress and immune evasion. Current research is limited by overreliance on single-disease models. Predominant reliance on isolated disease models fails to recapitulate ER stress dynamics in comorbid conditions. Inadequate representation of multiorgan interactions and systemic pathological cascades. The barriers to clinical translation remain significant. The complexity of ER stress-related signaling networks complicates target identification and validation. Scarcity of large-scale clinical trials and standardized biomarkers for assessing treatment efficacy. Differences between species give rise to safety concerns for clinical administration. Divergent drug responses between animal models and human physiology limit predictive accuracy. Potential off-target effects of ER stress modulation on normal cellular homeostasis require rigorous evaluation. Future strategies emphasize cross-disease integration through multiomics and systems biology. Precision therapeutics could leverage genomic/proteomic profiling for patient-specific UPR pathway modulation. Innovations such as nanogel-based drug carriers and ER stress-responsive vaccines may enhance spatiotemporal control and synergize with immunotherapy. Advanced models, including CRISPR-edited organoids, multidisease murine systems, and organ-on-chip platforms, aim to replicate human pathophysiology and tumor-immune interplay First, in cancer research, aberrant activation of ER stress sensors and their upstream and downstream signaling pathways has become a key regulator of tumor growth and metastasis, as well as the response to chemotherapy, targeted therapy, and immunotherapy. Findings have consistently shown that rational control of the ER stress response can significantly inhibit tumor progression by promoting malignant apoptosis and enhancing the immune response. Therefore, a deeper understanding of the precise molecular mechanisms by which ER stress affects immune cell function may greatly improve the efficacy of cancer immunotherapy in the clinical setting. Although breakthroughs in IRE1-, PERK-, and BiP-based immunosuppression studies have been reported in recent years, information on the upstream and downstream modalities of ATF6 regulation is lacking. The detailed mechanisms by which ATF6 functions in T and B cells have not been fully elucidated. Exploring the impact of ATF6 on immune cells is crucial. Furthermore, the impact of immune cell spatial localization within tumors on the ER stress response remains to be demonstrated. While single-cell omics techniques have decoded intratumor heterogeneity, they do not preserve the spatial coordinates of cells. Spatial omics, which provides precise cellular and molecular localization information, is revolutionizing our understanding of the cancer environment. The application of spatial histology techniques to explore the effects of ER stress on immune cells in the TME has the potential to provide innovative solutions for designing precision medicine strategies. Second, most studies have focused on single-disease models and lack a comprehensive analysis of multiple disease interactions. This limitation not only affects our understanding of ER stress mechanisms but also restricts the clinical application value of the findings, especially when multiple disease pathologic states are involved. Single-disease models are usually created under laboratory conditions for specific disease states, such as T2D, AD, or HF. These studies often provide insight into the mechanism of action of ER stress in the context of a specific disease. However, this approach ignores the reality that many patients have multiple diseases simultaneously. For example, metabolic syndrome, as a complex pathological state, involves multiple aspects of obesity, diabetes, hypertension, and dyslipidemia. In the context of metabolic syndrome, ER stress may not only be a consequence of disease occurrence but also interact with different pathologic states. For example, IR and adipocyte dysfunction may lead to increased ER stress, exacerbating diabetes and cardiovascular disease. However, most current studies have neglected these interactions, resulting in our inability to fully understand the true role of ER stress in the context of complex diseases. In addition, combining multidimensional data from genomics, transcriptomics, proteomics, and metabolomics to construct comprehensive models of ER stress-related diseases can lead to a better understanding of the molecular mechanisms of complex diseases. Third, by monitoring the extent of ER stress and the corresponding biomarkers, it is possible to understand the regulation of the intracellular environment by treatment, which can inform the assessment of efficacy in clinical trials. However, we also found a need for clinical trials on ER stress, one of the major reasons being that ER stress involves multiple signaling pathways and regulatory factors and that its molecular mechanisms are complex and still need to be fully understood. This complexity adds to the technical challenges of applying it to clinical trials. In particular, assessing the activity and impact of ER stress requires the use of specific experimental techniques and biomarkers, which increases the difficulty of implementing appropriate clinical trials. Moreover, the translation of ER stress research into clinical trials is in its early stages and requires further in-depth research and validation. Existing clinical studies related to ER stress are particularly rare. In addition, established clinical studies of ER stress often rely on small experimental or clinical samples, which may result in findings that are not statistically significant or lack generalizability. ER stress research necessitates multidisciplinary collaboration, spanning the fields of cell biology, immunology, and clinical medicine. Therefore, when relevant clinical trials are conducted, expertise and resources from different fields must be integrated to ensure the scientific validity and feasibility of the study design. Finally, current research suggests that there may be differences in the response to and tolerance of different individuals to ER stress, which poses a challenge for clinical application and individualized therapy. Although many ER stress-related studies rely on animal models (e.g., mouse models), the physiological states and stress responses of these animal models differ from those of humans, particularly in terms of drug response, the immune system, and organ specificity. The therapeutic effects of drugs targeting ER stress observed in animal models may not be fully replicated in clinical human cases. Furthermore, ER stress interventions and modulation may affect normal cellular functions. Consequently, in-depth studies are needed to ensure treatment safety and efficacy. In future studies, the following aspects should be emphasized (Fig. 7 ). First, comprehensive cross-disease modeling studies are needed to better understand the role of ER stress in different pathological states. Such studies can reveal the interactions between ER stress and other cellular stress pathways and help us understand the complexity of the disease. Second, the personalization of targeted therapy is important. Future therapeutic strategies should consider patients’ genetic backgrounds and specific pathological states to develop personalized, targeted drugs. Genomics and proteomics research can identify potentially effective therapeutic targets in specific patient populations. In addition, there is a need for continued focus and development of novel drugs that are more effective in modulating ER stress and have fewer toxic side effects. This is where the link between basic research and clinical applications needs to be strengthened to facilitate the translation of research results. Third, fluorescent probes, nanogel drugs, and tumor vaccines targeting ER stress are still in the early stages of development. The fluorescent probe can accurately identify the type of ER stress-producing cells and precisely trigger ER stress in tumor cells to accelerate their apoptosis. Compared with conventional treatments, nanogel drugs can deliver the encapsulated drug to the lesion site and reduce the toxic response to normal tissues. In addition, tumor vaccines, emerging personalized immunotherapies that autonomously stimulate the immune system for treatment, may lead to long-lasting therapeutic effects and protection against future tumor recurrence. Making ER stress tumor vaccines available for clinical use requires rigorous clinical trials to evaluate their safety, efficacy, and applicability, which is one of the important tasks ahead. Finally, complex animal models, such as gene-edited animals, conditionally transgenic animals, and multiple disease models, are essential. The success of animal experiments does not always translate into clinical efficacy, mainly because of the complex environment in vivo and the differences between different organisms. Therefore, there is no substitute for increasingly complex animal experiments. In conclusion, ER stress plays an important role in the occurrence and development of a variety of diseases, and in-depth studies of its mechanism have provided new ideas for targeted therapy. Although current studies have progressed, many challenges and limitations still exist. Future development should focus on the establishment of multiple disease models, the exploration of personalized therapy, the development of novel drugs, and improvements in the design of clinical studies. These efforts are anticipated to lead to significant breakthroughs in targeted ER stress research and treatment, offering new opportunities for the prevention and treatment of related diseases.

ER stress is increasingly recognized as a key factor in the pathogenesis of a wide range of diseases. The intricate balance between ER stress and UPR activation underscores the potential for therapeutic interventions targeting this pathway. This chapter explores various biomarkers and therapeutic approaches to target ER stress. First, we address potential biomarkers of ER stress that can be used to diagnose or monitor treatment outcomes. We discuss agents developed to alleviate ER stress. The actions of these agents range from enhancing protein folding to modulating UPR signaling pathways. Next, we describe clinical trials focused on modulating ER stress. Finally, novel drugs and innovative therapies that are promising for addressing ER stress are highlighted. The identification of ER stress biomarkers has become a critical tool for diagnosing disease and evaluating treatment response. These biomarkers not only reflect the activation status of the UPR but also provide actionable insights into disease progression and treatment efficacy. We categorize ER stress biomarkers according to their molecular properties, present their clinical validation, and describe their application in precision medicine. As dynamic indicators of ER stress, different molecular features generated by the UPR pathway are fundamental components of ER stress biomarkers. Key candidate molecules include ER chaperones, UPR effectors, and apoptosis markers. GRP78, GRP94, and calreticulin act as chaperones whose expression increases during early ER stress to assist in protein folding. GRP78 has been shown to act as a biomarker of tumor behavior and response to therapy, and its upregulated expression promotes tumor proliferation, survival, metastasis, and resistance to various therapies. 374 Clinically, elevated GRP94 expression is associated with an aggressive phenotype in a variety of cancers and not only promotes survival signaling but also regulates immune responses through multiple pathways. Therefore, GRP94 is a potential molecular marker and therapeutic target for malignant tumors. 375 Calreticulin is a chaperone protein present in the ER, and its exposure plays a broad role in immune surveillance. Studies have shown the potential significance of calreticulin, which is present on the surface of dying tumor cells, as a prognostic biomarker for ovarian cancer patients. 376 Among the effectors, splicing XBP1, phosphorylating eIF2α, and cleaving ATF6 directly correlate with the degree of UPR activation. Detection of spliced XBP1 mRNA is often used as a quantitative method for measuring ER stress. 377 Zhao and colleagues specifically observed XBP1 splicing/activation in TAMs, which led to protumorigenic cytokine expression and promoted CRC growth and metastasis. Therefore, targeting XBP1 signaling in TAMs may be a potential strategy for CRC treatment. 242 In prostate cancer, phosphorylation of eIF2α converts overall protein synthesis to levels that promote aggressive tumor development and is a marker of poor patient survival. 378 Recent evidence emphasizing the protective role of ATF6 in adverse outcomes associated with I/R injury suggests that ATF6 is a biomarker for intervention in a variety of ischemia-associated disorders and that targeting ATF6 intervention has the potential to predict such disorders. 288 Apoptosis, a common outcome of ER stress, is mediated by the PERK pathway through the upregulation of CHOP and caspase-12 during the terminal UPR. 379 , 380 In addition, increased CHOP mRNA in clinical samples is also a biomarker of poor prognosis in chemotherapy-treated rhabdomyosarcoma patients. 381 Many ER stress biomarkers have been used in clinical diagnosis and treatment monitoring. Nourbakhsh et al. reported significantly elevated serum GRP78 levels in patients with T2D (1.3-fold greater than those in controls) and high diagnostic accuracy. 382 In hepatocellular carcinoma, Lim et al. reported that the expression of GRP78 and GRP94 increased with increasing cancer progression and was significantly associated with vascular infiltration and intrahepatic metastasis. 383 In 2010, Bagratuni’s team correlated the gene expression levels of XBP1 unspliced (XBP1u) and XBP1 spliced (XBP1s) with clinical outcomes, with patients with low XBP1s/u ratios predicting high survival. Researchers have also reported that patients with low XBP1s/u ratios respond better to thalidomide treatment, and the survival of patients in the low-ratio group treated with thalidomide was significantly better than that of patients in the conventional chemotherapy group. 384 In addition, ER stress biomarkers are not only diagnostic tools but also tools to guide targeted therapy. XBP1 is highly advantageous for predicting drug response. In 2013, Tiedemann et al. explored the mechanisms of proteasome inhibitor (PI) resistance in MM and reported that myeloma patients with higher levels of XBP1s at baseline responded better to proteasome inhibitors. 385 In monitoring treatment efficacy, Jagannathan and colleagues reported that HSPA5, which encodes GRP78, was highly expressed in patients who did not respond to bortezomib treatment, suggesting that high expression of GRP78 is a potential marker of resistance and that detecting the level of HSPA5 expression in the tumors of first-time patients predicts their probability of responding to bortezomib. Moreover, monitoring the dynamic changes in GRP78 during treatment could provide a basis for adjusting the drug dosage or combining drugs (e.g., adding autophagy inhibitors) to overcome drug resistance. 386 In summary, the identification of ER stress biomarkers not only provides a tool for early diagnosis and typing of the disease but also allows dynamic evaluation of therapeutic efficacy, guides individualized treatment, and promotes the development of drugs targeting the ER stress pathway. With the advancement of multiomics technology, its value in precision medicine will be further enhanced. The development of preclinical drugs that target ER stress represents a crucial frontier in therapeutic innovation, particularly for diseases characterized by protein misfolding and cellular dysfunction. Recent advances in understanding the molecular pathways involved in ER stress have led to the identification of specific targets for drug development, allowing researchers to create small molecules that can increase chaperone activity or inhibit proapoptotic signaling. By focusing on these pathways, preclinical drug candidates show promise in alleviating the burden of diseases, providing a foundation for future clinical applications (Fig. 6 ). Fig. 6 Common therapeutic agents that target ER stress and modify tissue cells. UPR pathway modulators produce therapeutic effects against different diseases. Common types of inhibitors include inhibitors that target the IRE1 ribonuclease and protein kinase structural domains, ATF6 inhibitors, PERK/eIF2α inhibitors, and BiP inhibitors. The efficacy of these inhibitors is demonstrated by their ability to induce apoptosis in damaged cells, enhance the antitumor function of immune cells, increase antiangiogenic effects, decrease cytotoxicity, attenuate inflammatory responses, reduce nerve cell mortality, and restore cell viability. Classical concurrent chemoradiotherapy is a combination of chemotherapy and radiotherapy used to treat cancer, and combining ER stress inhibitors with chemoradiotherapy can enhance the therapeutic effects of both. In recent years, novel drugs that target ER stress, including cancer vaccines, fluorescent probes, and nanogel drugs, have been developed for the treatment of various diseases Common therapeutic agents that target ER stress and modify tissue cells. UPR pathway modulators produce therapeutic effects against different diseases. Common types of inhibitors include inhibitors that target the IRE1 ribonuclease and protein kinase structural domains, ATF6 inhibitors, PERK/eIF2α inhibitors, and BiP inhibitors. The efficacy of these inhibitors is demonstrated by their ability to induce apoptosis in damaged cells, enhance the antitumor function of immune cells, increase antiangiogenic effects, decrease cytotoxicity, attenuate inflammatory responses, reduce nerve cell mortality, and restore cell viability. Classical concurrent chemoradiotherapy is a combination of chemotherapy and radiotherapy used to treat cancer, and combining ER stress inhibitors with chemoradiotherapy can enhance the therapeutic effects of both. In recent years, novel drugs that target ER stress, including cancer vaccines, fluorescent probes, and nanogel drugs, have been developed for the treatment of various diseases Over the past decade, numerous preclinical and cellular studies targeting UPR signaling proteins have developed various inhibitors and chemotherapeutic agents. This section will detail several UPR pathway modulators known to produce antitumor effects across different cancer types. The efficacy of these inhibitors is demonstrated by altered amino acid metabolism, reduced vascular density, and decreased vascular perfusion, all of which contribute to their antitumor activity. 78 Notably, the simultaneous use of multiple target inhibitors against cancer cells has better efficacy. 387 The unique advantages of this combination therapy include controlling tumor progression and metastasis without damaging normal tissue. There are two common types of inhibitors of IRE1, including those that target the IRE1 ribonuclease and protein kinase structural domains. IRE1 ribonuclease inhibitors, including B-I09, STF-083010, MKC3946, MKC8866, and 4μ8C, have been extensively tested in CLL, MM, ALL, and ovarian cancer. 78 Sharing a common hydroxy-aryl-aldol (HAA) molecule, these inhibitors selectively target a specific lysine (Lys907) in the structural domain of the RNase, effectively preventing ER stress-induced site-specific mRNA splicing. 388 In a CLL mouse model, B-I09, which targets the IRE1-XBP1 pathway, led to XBP1 deficiency without affecting normal secretory or membrane-bound protein transport (Table 2 ). 35 Combining ibrutinib and B-I09 for treating human CLL has been shown to effectively inhibit leukemia progression without systemic cytotoxicity. 389 Moreover, B-I09 has improved the treatment of c-MYC- and N-MYC-driven malignancies, as demonstrated in model experiments. 390 In 2011, STF-083010 was used in MM studies as a small molecule inhibitor that specifically suppressed IRE1 endonuclease activity without affecting kinase activity. 30 The fourth-generation salicylaldehyde inhibitor MKC8866 targets the RNase structural domain of IRE1 for pharmacological inhibition (Table 2 ). 391 In a mouse model of ALL, the tyrosine kinase inhibitors (TKIs) nilotinib and MKC8866 act together in ALL cells. This combination enhances cell viability through synergistic induction of cytotoxicity. 392 Additionally, Xiao et al. proposed a combination drug approach for treating ovarian cancer last year, with promising results for the immune checkpoint inhibitors (ICIs) AZD1775 and MKC8866 in multiple cell lines and preclinical models of ovarian cancer. 393 The dual action on the UPR signaling pathway significantly enhanced tumor cell apoptosis, surpassing single drug delivery and offering a therapeutic opportunity for synergistic effects between AZD1775 and MKC8866. Finally, 4μ8C gains selectivity by forming an abnormally stable Schiff base with lysine 907 in the structural domain of the IRE1 endonuclease, which blocks substrate access to the active site of IRE1, leading to the inactivation of XBP1 splicing and IRE1-mediated mRNA degradation (Table 2 ). 32 The treatment of hepatocellular carcinoma mice suffering from fibrosis with 4μ8C significantly reduced the tumor burden and restored collagen to healthy baseline levels. Table 2 Delivery strategies for ER stress-targeted drugs Name Category Delivery Pathway Oncolytic viruses Injectable delivery Gene vector PERK/eIF2α B-I09 Injectable delivery Gene vector IRE1/XBP1 Paclitaxel Nanocarrier Nanomicelle eIF2α phosphorylation CB-5083 Nanocarrier Solid lipid nanoparticle ATF6, IRE1/XBP1 Amikagel Nanocarrier Nanoparticle CHOP EMT-NP Nanocarrier Nanoparticle IRE1, CHOP Au/Toy@G3 NGs Nanocarrier Nanogel IRE1/XBP1 ISRIB Biogenic vector Retroviral vector eIF2α phosphorylation MKC3946 Unspecific pLKO.1 shRNA vector IRE1/XBP1 MKC8866 Unspecific pGL3-MYC luciferase reporter plasmid plus either empty vector (pCDNA3) IRE1 RNase domain 4μ8C Unspecific Expression vectors encoding preprotrypsin-FLAG-HsIRE1[19–977] wild type IRE1 endonuclease KIRA8 Unspecific pET-28a vector IRE1 Kinase Fluvastatin Unspecific β-gal-LacZ expression vector GRP78 Delivery strategies for ER stress-targeted drugs The second class of inhibitors targets the structural domain of the IRE1 kinase and consists mainly of KIRA6, KIRA7, and KIRA8 of the kinase-inhibiting RNase attenuator (KIRA), which act by binding to the ATP pocket in the kinase structural domain. KIRA6, in a dose-dependent manner, inhibits IRE1 and XBP1 RNA cleavage, thereby improving cell survival under ER stress. 34 KIRA7 has been used in relatively few applications. KIRA8, also known as compound 18, selectively decreases the viability of patient-derived MM cells without significantly affecting normal cells (Table 2 ). 394 In a mouse model of established MM, KIRA8 treatment significantly reduced the tumor burden, demonstrating substantial in vivo efficacy. Notably, KIRA8 also improved the effectiveness of two established first-line antimyeloma drugs, bortezomib and lenalidomide, against MM. Experimental analysis of human MM cells by Yamashita et al. revealed that KIRA8 reduced cell viability and induced apoptosis, whereas its combination with bortezomib had greater antimyeloma effects. 395 KIRA8, in combination with anti-VEGF-A, an effective triple-negative breast cancer (TNBC) treatment, significantly decreases tumor growth, outperforming monotherapy. 218 Notably, compound 18 is the only agent to date that specifically targets cancer-associated fibroblasts (CAFs), a key cellular component associated with cancer progression. By disrupting IRE1, a key regulator within the CAF environment, this compound exerts its antitumor effects. These reports indicate that IRE1 RNase/kinase inhibitors can improve treatment outcomes, particularly in cases of poor chemotherapy response, drug resistance, and disease recurrence. The unique mode of action of these inhibitors offers far-reaching implications for developing revolutionary therapeutic approaches, paving the way for new cancer treatment strategies. Until Ceapin was developed by Gallagher et al. through a cell-based screening approach, the ATF6 signaling pathway was considered nonpharmacological. 396 It is the first inhibitor to selectively inhibit ATF6α without affecting other signaling pathways in the UPR and even without altering the viability of unstressed cells. Unlike conventional protease inhibitors, Ceapins do not inhibit ATF6α proteolysis and activation but instead eliminate the need for ATF6α trafficking from the ER by relocalizing Golgi-resident S1P and S2P proteases back to the ER. 397 Recently, this team revealed a novel mechanism underlying Ceapin specificity: an organelle-tethering mechanism that fosters a new morphological association between the ER and peroxisomes, paving new pathways for drug development and synthetic biology. 398 Compared with that of ATF6, the activity of the PERK/eIF2α signaling pathway is greater, which has prompted the development of targeted inhibitors. GSK2606414 was reported as the first PERK inhibitor. 33 As an oral, potent, and selective PERK inhibitor, it blocks the UPR pathway, reduces ROS production, and enhances cell viability. 399 In a mouse model, GSK2606414 reactivated T-cell function and reduced mitochondrial ROS in PD-1+ CD8+ TILs, improving CD8+ T-cell viability. 400 Notably, combining GSK2606414 with anti-PD-1 therapy resulted in a 100% survival rate. In addition to its antitumor effects, GSK2606414 has unique efficacy against astrocytes in certain neurological disorders, resulting in increased levels of the autophagy signaling protein P62, accumulation of the dipeptide repeats protein poly (GA) in deep neurons, DNA damage, and the occurrence of nuclear fission. 401 Similarly, GSK2656157 is an ATP-competitive PERK inhibitor. Yodsanit et al. first used GSK2656157 to treat AAA in 2023. 402 In the aneurysmal aortas of AAA patients, PERK is hyperphosphorylated, and the downstream proteins ATF4 and CHOP are significantly upregulated, while GSK2656157 effectively interferes with this process. Designed in 2015, AMG-44 is a potent, selective PERK-only inhibitor for exploring the PERK pathway both in vitro and in vivo. 403 Mohamed et al. evaluated the antitumor effects of GSK2606414 and AMG-44. 144 Mice treated with each inhibitor separately experienced similar tumor growth delays, with AMG-44 notably avoiding pancreatic toxicity. The reduced immunosuppressive activity of MDSCs under the modulation of AMG-44 caused an expansion of tumor-infiltrating CD8+ T cells expressing IFNγ, which greatly enhanced the antitumor capacity of these cells. LY-4, an emerging PERK inhibitor, significantly reduces PERK phosphorylation and nearly 90% reduces tumor growth upon administration. 404 LY-4 treatment is well tolerated in melanoma and has clear therapeutic potential, as evidenced by the absence of pancreatic damage in blood glucose level monitoring. Recently, discovered, ISRIB is a novel eIF2α inhibitor that activates eIF2B to inhibit eIF2α phosphorylation, improving the prognosis of neurological diseases and finding applications in cancer treatment. 405 In preclinical trials of prostate cancer, ISRIB significantly prolonged the survival of mice with metastatic tumors, although the effectiveness of ISRIB treatment against prostate cancer was transient. 378 It triggers cytotoxicity against aggressive metastatic prostate cancer cells through its selective reversal of the effects of eIF2α phosphorylation, notably without significant side effects. The latest study revealed that combining ISRIB with doxorubicin, owing to its ability to inhibit stress granule formation, significantly attenuates TNBC tumor growth through a synergistic effect. 406 In a study targeting pancreatic ductal adenocarcinoma, the PERK inhibitor GSK2606414 and the eIF2α phosphorylation inhibitor ISRIB significantly inhibited tumor growth with great potential to improve treatment outcomes. 407 In lung cancer, treating tumor cells with both inhibitors substantially decreased survival, mirroring the results observed in pancreatic ductal adenocarcinoma. 408 Given the significant role of pathways such as PERK/eIF2α/CHOP in maintaining organ homeostasis in hypersecretory tissues, it is crucial to consider their effects on normal tissues to minimize potential toxicity during treatment. Specifically, PERK inhibitors such as AMG-44 and LY-4, which are known for their tolerability and robust antitumor efficacy without detectable cytotoxic side effects, offer clear guidance for future inhibitor selection. Inhibitors against the three UPR pathways have been widely used, and targeted inhibitors of BiP, an essential protein for the initiation of the UPR, are being progressively developed. Given that BiP inhibitors bind to the three sensors of the UPR and render them inactive, there are already clinical applications for BiP inhibitors. KP1339, a ruthenium-based compound and BiP-targeted inhibitor, has shown promising anticancer activity in a phase I clinical trial. 409 Combining KP1339 with sorafenib, a classic liver cancer treatment, induced significant synergistic effects, enhancing tumor cell apoptosis. 410 Recently, KP1339 was also found to trigger ICD features in colorectal cancer, as indicated by PERK and eIF2α phosphorylation, calmodulin exposure on cell membranes, and the release of high mobility group box 1 and ATP. 411 KP1339 has shown preclinical activity across various tumor types, with acceptable tolerance and disease stability, despite some mild side effects. The discovery of KP1339 provides support for the integration of metabolomics with immunotherapy. Despite the obscure role of metal-based drugs in modulating antitumor responses, they offer new possibilities in the burgeoning field of cancer therapy. Cerezo et al. developed a series of molecules (thiazole benzenesulfonamides) that promote melanoma cell death by targeting the ER stress pathway. Histocompatibility antigen 15 (HA15), which is the main component, is a highly selective BiP inhibitor that interacts only with BiP without affecting IRE1, PERK, or ATF6. 412 HA15 reduces BiP levels in the immunoprecipitated fractions of PERK, IRE1, and ATF6 and inhibits BiP ATPase activity in a dose-dependent manner. Importantly, HA15 is effective against BRAF inhibitor-resistant melanomas and tumor cells with high BiP levels, slowing their progression. A recent study also suggested that genetic inhibition of BiP not only reduces tumor growth but also contributes to tumor suppression by sensitizing colon cancer cells to BRAF inhibitor-induced ER stress and apoptotic responses. 413 Moreover, Samanta et al. reported that YUM70, a hydroxyquinoline analog, induces ER stress-mediated apoptosis in pancreatic cancer by binding to BiP and inhibiting its ATPase activity. 39 YUM70 showed superior efficacy against pancreatic cancer in both in vivo and in vitro experiments, as it selectively inhibited tumor growth without affecting normal tissue. Researchers have combined YUM70 with the clinically approved drugs topotecan and vorinostat to treat pancreatic cancer. This combination revealed strong synergistic effects, increasing both early and late apoptosis. Targeting BiP with HA15 and YUM70 effectively treats lung and colon cancers with KRAS mutations, in addition to pancreatic cancer. 414 These studies provide strong evidence that BiP is a therapeutic target and highlight the potential of YUM70 as a therapeutic agent for pancreatic cancer. This chapter provides a comprehensive overview of the most commonly used ER stress pathway inhibitors in cancer therapy (Table 3 ). This discussion highlights the dual role of ER stress inhibitors in promoting apoptosis in malignant cells while sparing normal cells, thereby offering a therapeutic window. Overall, targeting ER stress pathways represents a promising strategy in cancer treatment, warranting further investigation into their clinical applications and potential synergistic effects with existing therapies. Table 3 ER stress pathway-related inhibitors Classification Name PMID Instruction IRE1 inhibitor B-I09 24812669 B-I09 is a water-soluble 1,3-dioxane derivative that effectively inhibits the expression of XBP1 and is a potent IRE1 RNase inhibitor. STF-083010 21081713 STF-083010 is a specific IRE1 endonuclease inhibitor without affecting its kinase activity. MKC3946 22538852 MKC3946 is an IRE1 endonuclease structural domain inhibitor that blocks XBP1 mRNA splicing and triggers growth inhibition in tumor cells. MKC8866 30679434 MKC8866 (IRE1-IN-8866), a salicylaldehyde analog, is a specific IRE1 RNase inhibitor with an IC50 of 0.29 μM for human IRE1 in vitro. 4μ8C 22315414 4μ8C (IRE1 Inhibitor III) is a potent and selective IRE1 Rnase inhibitor with IC50 of 76 nM. KIRA6 25018104 KIRA6 is a potent type II IRE1 kinase inhibitor with an IC50 of 0.6 μM. It dose-dependently inhibits IRE1(WT) kinase activity, XBP1 RNA cleavage, Ins2 RNA cleavage, and oligomerization. KIRA7 30625178 KIRA7 is an imidazopyrazine compound that binds to IRE1 kinase (IC50 of 110 nM) and inhibits its RNase activity in a metastable manner. KIRA7 has anti-fibrotic properties. KIRA8 28380378 KIRA8 (IRE1 inhibitor, AMG-18) is a mono-selective IRE1 inhibitor that allosterically attenuates IRE1 RNase activity with an IC50 of 5.9 nM. ATF6 inhibitor Ceapin-A7 27435962 Ceapin-A7 is a selective and highly potent inhibitor of ATF6, which can activate the response to ER stress, with an IC50 of 0.59 μM. PERK/eIF2α inhibitor GSK2606414 22827572 GSK2606414 is an orally available, potent, and selective PERK inhibitor with an IC50 of 0.4 nM, displaying at least 100-fold selectivity over the other EIF2AKs assayed. GSK2606414 impairs GANT-61-induced autophagy in NB cells with MYCN amplification. GSK2606414 exacerbates ER stress-induced apoptosis in HCT116 cells while reducing the apoptosis in SIL1 KD HeLa cells. GSK2656157 23333938 GSK2656157 is an ATP-competitive and highly selective inhibitor of PERK with an IC50 of 0.9 nM in a cell-free assay, 500-fold greater against a panel of 300 kinases. GSK2656157 decreases apoptosis and inhibits excessive autophagy. AMG-44 25587754 AMG-44 is a highly selective and orally active inhibitor of PERK with an IC50 of 6 nM. AMG-44 exhibits 1000-fold and 160-fold selectivity over GCN2 and BRAF, respectively. LY-4 27977682 LY-4 is a PERK-specific inhibitor with an IC50 value of 2 nM and little activity against other eIF2α kinases. ISRIB 23741617 ISRIB is an integrated stress response (ISR) inhibitor that potently reverses the effects of eIF2α phosphorylation. BiP/GRP78 inhibitor KP1339 12778081 KP1339 is a first-in-class ruthenium anticancer agent developed for solid cancers with low side effects. KP1339 induces G2/M cell cycle arrest, DNA synthesis blockade, and apoptosis via the mitochondrial pathway. KP1339 has a high tumor-targeting potential, binds strongly to serum proteins such as albumin and transferrin, and is activated in the reductive tumor environment. Thiazole benzenesulfonamides 27238082 HA15 is the lead compound of Thiazole benzenesulfonamides. The BiP/GRP78/HSPA5 chaperone is a specific target of HA15, leading to melanoma cell death by simultaneously inducing autophagy and apoptosis mechanisms. YUM70 33531374 YUM70 is a potent inhibitor of GRP78 with an IC50 of 1.5 μM. YUM70 induces ER stress-mediated apoptosis in pancreatic cancer. Although YUM70 inhibits GRP78 enzymatic activity, it increases the expression of GRP78 by increasing the chaperone translation mechanism. ER stress pathway-related inhibitors Classical concurrent chemoradiotherapy is a combination of chemotherapy and radiotherapy used to treat cancer. Lee et al. reported that the expression of the ER stress protein GRP78 has significant prognostic value in neoadjuvant radiotherapy for locally advanced rectal cancer. 415 Combining ER stress inhibitors with chemoradiotherapy can enhance the therapeutic effects of both drugs. Given the frequent overexpression of squalene epoxidase (SQLE) in human cancers, Hong et al. investigated a novel tumor-specific radiosensitizer targeting this enzyme. 416 Inhibiting SQLE to activate PERK/eIF2α-mediated translation triggers an ER stress response, promoting radiosensitization in breast and lung cancer cells. Furthermore, Guo’s team investigated the impact of ER stress pathway gene polymorphisms on the clinical efficacy of radiotherapy in nasopharyngeal carcinoma patients. Statistical analysis revealed that several genes, including XBP1, were significantly associated with primary tumor outcome 3 months after radiotherapy and with the occurrence of radiotherapy-induced myelosuppression and may serve as predictors of the clinical outcomes of radiotherapy in nasopharyngeal carcinoma patients. 417 Among common antitumor immunotherapies, ICI therapy has been extensively studied for its role in interfering with the ER to treat cancer. ICI therapy disrupts negative immune checkpoints and activates antitumor immune responses. 418 The antitumor immune response refers to a series of reactions and mechanisms of the body’s immune system against tumor cells aimed at recognizing, destroying, or controlling the proliferation and spread of tumor cells. 419 The discovery of predictive biomarkers is crucial, potentially expanding the range of patients benefiting from immune checkpoint blockade. ICI therapy not only enhances the antitumor immune response but also influences the intrinsic dynamics of the TME. 420 Recent research has shown that drugs targeting ER-associated biomarkers increase the efficacy of anti-PD-L1 immunotherapy. PD-L1, which is synthesized in the ER of tumor cells and is overexpressed in various cancers, enables tumor cells to evade antitumor immunity by inhibiting T-cell-mediated cytotoxicity. 421 Sun et al. reported that hepatocellular carcinoma cells mediate antitumor responses via ER stress-released exosomes. 422 Notably, miR-23a-3p, an upstream microRNA of PD-L1, inhibits T-cell function by upregulating PD-L1 in macrophages. Researchers subsequently revealed the potential of the thyroid adenoma-associated gene (THADA) as a biomarker in colorectal cancer cells. 423 Targeting THADA leads to PD-L1 degradation via the ER, remarkably increasing T-cell-mediated cytotoxicity. An early study indicated that metformin-activated AMPK directly phosphorylates S195 of PD-L1 and that its phosphorylation induces ER stress, which promotes antitumor immunity through PD-L1 degradation. 424 Importantly, ER-targeted therapies have been shown to activate the immune system and enhance anti-PD-L1 therapy, motivating further exploration of ER stress-related biomarkers. 425 Guttman et al. treated tumor-bearing mice with an anti-mouse PD-L1 monoclonal antibody and an IRE1 inhibitor but only partially inhibited tumor progression. 426 Combining these agents was significantly more effective than either treatment alone. Therefore, synergizing IRE1 inhibition with anti-PD-L1 antibody therapy significantly contributes to tumor regression. Additionally, IRE1/XBP1 pathway inhibitors may enhance PD-1 antibody therapy. IRE1/XBP1 pathway inhibitors repolarize M2-TAMs in response to ER stress and oxidative stress, greatly increasing immunotherapy sensitivity. 427 This approach not only slows tumor growth but also enhances the effectiveness of anti-PD-1 therapy. B-I09, in combination with anti-PD-1 antibodies, particularly targets coactivator-associated arginine methyltransferase 1 (CARM1)-expressing ovarian cancer cells, increasing treatment efficacy. 428 This combination therapy significantly outperformed monotherapy in reducing the tumor load and improving survival in tumor-bearing mice. Additionally, Yang et al. reported that paclitaxel (PTX) treatment activates the PERK/eIF2α pathway, as evidenced by ER stress-related gene expression and immune cell profile analysis in treated tumors (Table 2 ). 429 Consequently, low-dose PTX and PD-1 antibody combination therapy was proposed to stimulate CD8+ T-cell-dependent antitumor immunity, significantly improving treatment efficacy. A study also revealed that SCD1 inhibitors enhance the therapeutic effects of immunotherapy by impairing ER stress. 430 SCD1 inhibitors reduce ER stress, enhancing antitumor T-cell production and increasing the therapeutic effect of anti-PD-1 antibodies. These studies highlight that single anti-PD-1/PD-L1 therapy is insufficient for optimal efficacy, making combination therapy a promising research direction. Advanced cancer phototherapy techniques, when combined with ICI therapy, inhibit tumor growth. Photosensitizers activate ER stress and ICD, potentiating the antitumor immune response without inducing cytotoxicity. 431 When combined with oxaliplatin, an ICD inducer, researchers reported significant enhancement of tumor immunogenicity. A study has shown that the ER stress response triggers ICD, inducing a protective antitumor immune response, with a significant focus on the PERK axis of the UPR. 432 Mohamed et al. reported that deleting PERK signaling transforms MDSCs into myeloid cells, increasing CD8+ T-cell-mediated anticancer responses. 144 Therefore, pharmacologically inhibiting PERK in melanoma cells stimulates potent activation of antitumor T-cell immunity. Furthermore, eliminating PERK in malignant cells triggers SEC61β-induced apoptosis, inhibiting tumor growth. 433 Consequently, combining ICD with ER-related inhibitors as part of a combinatorial therapeutic strategy shows promising efficacy and prognosis. In recent years, through optimization and improvement, chimeric antigen receptor (CAR)-T cells have achieved very good results in clinical tumor therapy. 434 Ibanez’s team reported that the ER stress response gene GRP78 may be a promising target for CAR-T-cell therapy. In vitro and in vivo experiments confirmed that GRP78-CAR-T cells can recognize and kill brain tumors, while the significant upregulation of GRP78 in CAR-T cells also increased their therapeutic response. 435 In addition, cell-surface GRP78-targeted CAR-T cells were also demonstrated to eliminate lung cancer tumor xenografts by Wang et al. The results showed that cell-surface GRP78-targeted CAR-T cells could effectively kill lung cancer cells without any recurrence or harmful effects. 436 ER stress plays an important role in the development of cardiovascular diseases. When cardiomyocytes are exposed to stimuli such as oxidative stress, ischemia, or inflammation, ER dysfunction may lead to impaired protein folding, which in turn induces apoptosis and cardiac injury. In recent years, researchers have reported that drugs targeting ER stress can effectively improve the prognosis of cardiovascular disease patients. These drugs provide new therapeutic ideas by modulating the folding ability of the ER, enhancing cell survival signaling, or attenuating inflammatory responses, providing new hope for patients with cardiovascular disease. Salvianolic acid B (SalB), a water-soluble substance and the main bioactive compound in Salvia divinorum, has antioxidant and anti-inflammatory effects and has been used to treat atherosclerosis. 437 Chen et al. demonstrated that SalB pretreatment significantly prevented doxorubicin-induced intracellular calcium ion disturbances, mitochondrial membrane potential disturbances, and elevated levels of ER stress-related proteins in mouse heart cells. 438 This cardioprotective effect mainly attenuated ER stress by inhibiting TRPC3- and TRPC6-mediated calcium overload in cardiomyocytes. 439 Fluvastatin can induce a cytoprotective UPR, as evidenced by the protection of macrophages from hypoxia-induced cell death via GRP78 induction, which contributes to the treatment of advanced atherosclerosis (Table 2 ). 440 Many reports have shown that atorvastatin attenuates ER stress-related protein levels. 441 In the presence of myocardial I/R, it can reverse the expression of SIRT1, block the ER stress pathway, and improve cardiomyocyte survival. 442 Metformin, a traditional antidiabetic drug, also reduces cardiac injury during I/R. It attenuates cardiac injury during ER stress primarily by protecting cardiac mitochondria and inhibiting CHOP expression. 443 Ginkgolide K can limit ER stress damage by increasing IRE1/XBP1 activity in cardiomyocytes, which leads to ER-related degradation-mediated clearance of misfolded proteins and increased autophagy. 444 Ginkgolide K was also able to partially inhibit the proapoptotic effects of the IRE1-dependent decrease and the JNK pathway, which could be effective in the treatment of MI. Recent reports indicate that TUDCA and sildenafil can restore the expression levels of ER stress pathway genes (XBP1, ATF4, and ATF6) and ER stress targets (HSPA5, DDIT3, and DNAJC3). 445 Stabilization of ER function leads to the rescue of mitochondrial respiratory defects, oxidative stress, and apoptosis, which helps early-stage HF patients. George et al. reported that β-adrenergic antagonists reduce ER stress and normalize calcium handling; among these effects, metoprolol improves cardiac function by decreasing the expression level of eIF2α, which is beneficial in HF. 446 Liu et al. assessed apoptosis in the heart after treating mice with the selective eIF2α dephosphorylation inhibitor salubrinal and reported that salubrinal reduced ER stress and myocardial apoptosis, which could be used to treat HF. 447 The inhibition of cGMP-specific phosphodiesterase 5 (PDE5) with sildenafil was shown to have beneficial effects on HF in a study by Gong et al. 448 The main mechanism is that sildenafil inhibits the expression of PERK, GRP78, and XBP1 to prevent ER stress, thereby reducing cardiomyocyte apoptosis. Curcumin has been frequently reported to prevent a variety of heart diseases. 449 Its cardioprotective mechanism is related to the reduction in palmitate-induced apoptosis in cardiomyocytes, which occurs mainly through the inhibition of ER stress-related signaling pathways through the downregulation of GRP78 and CHOP. 450 Recently, Li’s team validated the principle of tauroursodeoxycholic acid (TUDCA) in the treatment of obese cardiomyopathy, which attenuates intracellular calcium abnormalities and regulates ER stress by downregulating the expression of GRP78, eIF2α, and ATF4. 451 TUDCA can also be used to treat obese cardiomyopathy patients. In addition, TUDCA alleviated myocardial inflammation by inhibiting the IRE1-associated NF-κB pathway, exerting a protective effect on cardiomyocytes, which is very important in the study of cardiovascular diseases. 452 The sodium‒glucose cotransporter 2 (SGLT2) inhibitor ertugliflozin can attenuate ER stress by inhibiting the mTOR pathway. 453 SGLT2 inhibition attenuates elf2α and downstream ATF4 and CHOP signaling, leading to reduced left ventricular apoptosis and fibrosis, a newly recognized cardioprotective mechanism. Dapagliflozin is also used as an SGLT2 inhibitor in the treatment of diabetic patients, and it also reduces the expression of ER stress- and apoptosis-related proteins in high glucose-induced cardiomyocytes. 454 In addition, metformin has been shown to attenuate ER stress in vascular smooth muscle cells by inhibiting the expression of XBP1, eIF2α, and GRP78, thereby alleviating hypertension. 455 In summary, therapeutic strategies targeting ER stress show great promise in the management of cardiovascular disease. Although this topic is still in the research stage, through a deeper understanding of the mechanism of ER stress and its role in cardiovascular disease, more effective and safer drugs are expected to be developed in the future. This will not only improve the quality of life of patients but also help reduce the morbidity and mortality of cardiovascular diseases. ER stress is a key factor in the development of neurodegenerative diseases. Nerve cells activate the ER stress response when faced with oxidative stress, protein aggregation, and metabolic imbalance, a process that, if uncontrolled, may lead to apoptosis and dysfunction. In recent years, researchers have shown that drugs that target ER stress can provide new therapeutic avenues by improving the folding capacity of the ER, promoting protein degradation, and reducing neuroinflammation. In 2024, Goswami et al. used integrated stress response inhibitor B (ISRIB) to attenuate ER stress-mediated inflammation, neurodegeneration, and cognitive deficits in AD rats by downregulating the expression of ATF4 and CHOP (Table 2 ). 456 This study suggests that ISRIB may serve as a potential drug for the treatment of AD. Rosiglitazone attenuates amyloid β-induced BiP and CHOP-induced ER stress through PPARγ-dependent signaling, thereby protecting human neural stem cells from amyloid β-mediated toxicity, and this study may contribute to the development of new strategies for the treatment of AD. 457 In a study exploring the mechanism of rivastigmine in the treatment of AD, Gupta et al. reported that the levels of ER stress-related markers (GRP78, GADD153, and caspase-12) were significantly inhibited, which could reduce neuronal apoptosis. 458 Recently, the mechanism of repaglinide in PD therapy was first explored by Motawi et al. 459 By decreasing BiP/ATF6/CHOP and caspase-3 levels, repaglinide attenuates striatal ER stress and apoptosis, suggesting that repaglinide has a protective effect on neuronal cells in PD rats. Pharmacological inhibition of the PERK inhibitor GSK2606414 is neuroprotective against PD caused by PTEN-induced putative kinase 1 (PINK1) mutations, which are caused mainly by the inhibition of defective mitochondrial-activated ER stress, thereby attenuating neurotoxicity. 460 Rosiglitazone significantly increased the survival of neuroblastoma cell lines, which is neuroprotective in mutant Huntington protein-expressing cells. 461 Glucocorticoids can antagonize ER stress-induced apoptosis and prevent HD-mediated neurodegeneration by reducing the expression of eIF2α and CHOP, which highlights the potential of glucocorticoids in the treatment of neurodegenerative diseases. 462 In summary, therapeutic strategies targeting ER stress offer new ideas and possibilities for intervention in neurodegenerative diseases. These drugs not only show promising results in slowing the course of the disease and improving neurological function but also may reduce neuronal cell mortality by modulating the ER stress response. With a deeper understanding of pathogenesis, more effective and safe drugs are expected to be developed in the future. ER stress plays an important role in the development and progression of several metabolic diseases. When it is dysregulated, it triggers cell death, inflammatory responses, and metabolic diseases. Therefore, therapeutic strategies targeting ER stress are gradually gaining attention, and researchers are developing novel drugs to modulate ER function to improve the pathology of related metabolic diseases. Recently, TUDCA was found to ameliorate high-fat diet-induced obesity and IR by inhibiting ER stress in peripheral tissues, which is a novel application scenario for TUDCA. 463 SalB, an antioxidant that is commonly used to treat cardiovascular diseases, has also been reported to possibly be used to treat IR by improving glucose tolerance. 464 Shi et al. proposed that the mechanism by which SalB ameliorates IR is dependent on ER stress, as evidenced by the attenuation of BiP and CHOP transcription as well as the phosphorylation of PERK and IRE1 in the livers of obese mice. Curcumin, a natural polyphenolic antioxidant compound, inhibits adipose tissue ER stress by dephosphorylating IRE1 and eIF2α and reduces cAMP accumulation by retaining phosphodiesterase 3B induction. 465 The attenuation of ER stress via the cAMP/protein kinase (PK) A pathway, improved insulin sensitivity and reduced lipolysis of fat are all evidence for its use in preventing hepatic IR. Liraglutide and dulaglutide are both glucagon-like peptide 1 (GLP-1) receptor agonists that improve glycemic control by promoting insulin secretion and attenuating ER stress, which is a new finding in the treatment of IR. 466 Liraglutide can improve endothelial cell function by decreasing the levels of eIF2α and IRE1; increasing the expression of genes related to cell differentiation, proliferation, and anti-apoptosis; and inhibiting the expression of genes related to pro-apoptosis, which can effectively reduce IR. 467 Lei et al. reported a significant decrease in IRE1 and ATF6 protein levels in alpha-lipoic acid-treated HepG2 cells, which reduced mitochondrial dysfunction and thus improved IR. 468 SGLT2 inhibitors, which have been very popular in diabetes research in recent years, can promote ER robustness by preventing ER stress response failure. 469 Canagliflozin (CANA), an SGLT2 inhibitor, restored ER homeostasis by maintaining sarco/ER Ca2+-ATPase activity, restoring the localization of GRP78, and downregulating the expression of eIF2α, ATF4, and CHOP. Recently, Zhang’s team verified that resveratrol, a natural polyphenol, protects insulin secretory function through the ER stress-related PERK pathway, with potential antidiabetic and antiobesity effects. 470 N-acetylcysteine (NAC) has a strong antioxidant effect in vivo, and it can significantly reduce the expression level of CHOP to treat T2D by restoring the function of ER homeostasis. 471 In addition, metformin is one of the most common classical drugs used for the treatment of T2D. Diaz-Morales et al. demonstrated that it modulates ER stress and autophagy in leukocytes from T2D patients, with a particularly pronounced effect on XBP1 and eIF2α. 472 In addition, metformin reversed ER stress, oxidative stress, and endothelium-dependent relaxation injury in mice fed a high-fat diet, thereby protecting endothelial function in obese diabetic mice. 473 Sitagliptin, a selective dipeptidyl peptidase-4 (DPP-4) inhibitor, improves endothelial function by promoting cell proliferation, attenuating the CHOP pathway in ER stress, and reducing high-fat diet-induced endothelial cell dysfunction and apoptosis in the thoracic aorta. 474 Combination therapy with sitagliptin and DA-1241 can achieve better results. Dapagliflozin, another SGLT2 inhibitor, attenuates hepatic oxidative stress and inflammation as well as hepatic and pancreatic ER stress and apoptosis in obese rats, with important implications for treating obesity and metabolic syndrome. 475 Overall, metabolic disease therapeutic drugs that target ER stress provide new clinical hope. These drugs have potential therapeutic effects by attenuating ER stress, enhancing cellular resistance, and improving metabolic pathways. With a deeper understanding of the mechanisms of ER stress, these drugs are expected to become novel therapeutic options for treating metabolic diseases, resulting in improved quality of life and improved patient prognosis. Recent studies have shown that ER stress plays an important role in the pathogenesis of autoimmune diseases. The cellular dysfunction and inflammatory response triggered by ER stress may exacerbate the autoimmune response and lead to tissue damage. Therefore, therapeutic strategies targeting ER stress have attracted widespread attention. Curcumin has anti-inflammatory and immunomodulatory effects in addition to alleviating IR. Zheng et al. reported that curcumin increased the expression of the ER stress-related transcription factors XBP1, ATF6, and CHOP in human CD4+ and Jurkat T cells. 476 This triggering of an excessive ER stress response can induce apoptosis in activated T cells and thus could be a promising treatment for autoimmune diseases. Last year, Chen et al. explored the mechanism of near-infrared photobiomodulation as a novel therapeutic strategy for RA. 477 It attenuates ER stress by decreasing ATF6 expression, thereby reducing the β-amyloid burden and ultimately improving cognitive function. In addition, the E3 ubiquitin ligase synoviolin (SYVN1) is responsible for synoviocyte growth during the development of RA. Earlier studies revealed that the inhibition of SYVN1 expression restored IRE1 protein expression, thereby reversing ER stress-induced apoptosis. 478 Li et al. reported that the inhibition of transient receptor potential melastatin 7 (TRPM7) activates ER stress, which induces FLS apoptosis in RA patients and could be a potential target for the treatment of RA. 479 Yousuf et al. experimentally reported that elevated expression of ER stress markers was detected in the dorsal root ganglion (DRG) neurons of MS patients and mice. 363 Chronic ER stress can lead to abnormal neuronal function and increased pain sensitivity. The levels of phosphorylated eIF2α, XBP1, and CHOP were significantly decreased in the DRG by 4-PBA treatment. In addition, 4-PBA indirectly reduces the activation of PERK, whose hyperactivation promotes neuronal excitability and pain through the phosphorylation of eIF2α. When PERK phosphorylation was selectively inhibited via AMG-44, the eIF2α signaling pathway was blocked, further validating the role of ER stress in MS pain. Rees et al. attempted to explore the effects of multiple medications on IBD. 372 The proinflammatory factor TNF-α upregulates the ER stress markers CHOP and GRP78 and enhances the sensitivity of TLR signaling by activating the NF-κB pathway. Azathioprine reduces the ER load in intestinal epithelial cells by inhibiting immune cell activity and decreasing the production of inflammatory factors. Azathioprine inhibits CHOP-mediated apoptosis in intestinal epithelial cells after reducing TNF-α and indirectly reduces XBP1s-driven UPR activation by inhibiting immune activation. In addition, infliximab alleviated ER stress-induced cell death by reducing inflammation, restoring the chaperone function of GRP78, and enhancing the protein-folding capacity of the ER. Ustekinumab can enhance ER protein folding by restoring ATF6 function. In conclusion, therapeutic agents targeting ER stress for autoimmune diseases have shown promising applications. Although still in the research and clinical trial stages, preliminary results have shown favorable safety and efficacy. We obtained detailed information on 27 clinical trials related to ER stress, including trial design, participant criteria, treatment regimens, and outcomes, as detailed in Table 4 . Table 4 Clinical trials of targeted ER stress NCT Number Applications Study URL Study Status Conditions Intervention method Phases Sample size Study Type Duration NCT03561831 Anesthesia in cancer https://clinicaltrials.gov/study/NCT03561831 COMPLETED Endoplasmic reticulum stress DRUG: Propofol|DRUG: Sevoflurane NA 53 INTERVENTIONAL 1 year NCT04628637 COVID-19 https://clinicaltrials.gov/study/NCT04628637 COMPLETED COVID-19 |Endoplasmic reticulum stress OTHER: Serum protein level analysis NA 144 OBSERVATIONAL 6 months NCT04455256 Recurrent pregnancy loss https://clinicaltrials.gov/study/NCT04455256 COMPLETED Recurrent pregnancy loss|Endoplasmic reticulum stress OTHER: X-box binding protein NA 90 OBSERVATIONAL 4 months NCT04440397 Endometriosis https://clinicaltrials.gov/study/NCT04440397 COMPLETED Endometriosis|Endoplasmic reticulum stress|Endometriosis-related Pain OTHER: XBP1 - endometriosis patients group NA 86 OBSERVATIONAL 5 months NCT02368704 Type 2 diabetes https://clinicaltrials.gov/study/NCT02368704 UNKNOWN Diabetes mellitus, type 2|Endoplasmic reticulum stress OTHER: No intervention NA 40 OBSERVATIONAL 4 days NCT04267809 Symptomatic viral infection https://clinicaltrials.gov/study/NCT04267809 COMPLETED Endoplasmic reticulum stress|Viral infection|Yellow fever DRUG: Metformin hydrochloride|DRUG: Calcium and vitamin D PHASE2 32 INTERVENTIONAL 2 years NCT06621901 Effect of protein on ER stress https://clinicaltrials.gov/study/NCT06621901 NOT_YET_RECRUITING Effect of high protein diet on endoplasmic reticulum stress OTHER: High protein diet|OTHER: Normal protein diet NA 20 INTERVENTIONAL 1 year NCT06025630 Hypertension https://clinicaltrials.gov/study/NCT06025630 RECRUITING Hypertension DRUG: TUDCA|DRUG: Placebo PHASE1|PHASE2 70 INTERVENTIONAL 5 years NCT01211015 Chronic respiratory diseases https://clinicaltrials.gov/study/NCT01211015 UNKNOWN ER stress,|Chronic airway disorders|Lung cancer|Interstitial lung diseases NA 50 OBSERVATIONAL undefined NCT04583631 Adenoid diseases https://clinicaltrials.gov/study/NCT04583631 COMPLETED Adenoiditis acute infective PROCEDURE: Adenoidectomy surgery NA 54 OBSERVATIONAL 9 months NCT04653376 Tonsillar tissue diseases https://clinicaltrials.gov/study/NCT04653376 COMPLETED Tonsillitis|Tonsillar hypertrophy|Immune system diseases PROCEDURE: Tonsillectomy surgery NA 46 OBSERVATIONAL 7 months NCT00771901 Metabolic function https://clinicaltrials.gov/study/NCT00771901 COMPLETED Insulin resistance|Diabetes|Obesity DRUG: tauroursodeoxycholic acid|OTHER: placebo|DRUG: sodium phenylbutyrate NA 101 INTERVENTIONAL 10 months NCT01807910 Nonalcoholic fatty liver disease https://clinicaltrials.gov/study/NCT01807910 WITHDRAWN Obesity|NAFLD DRUG: methyl-D9-choline EARLY_PHASE1 0 INTERVENTIONAL 6 months NCT04001647 Vascular dysfunction https://clinicaltrials.gov/study/NCT04001647 TERMINATED Vasodilation|Arterial stiffness DRUG: Acetylcholine|DRUG: Sodium Nitroprusside|DRUG: Ascorbic Acid EARLY_PHASE1 17 INTERVENTIONAL 1 year NCT02823184 Ph-negative myeloproliferative neoplasms https://clinicaltrials.gov/study/NCT02823184 COMPLETED Polycythemia vera|Essential thrombocythemia BIOLOGICAL: RNA sample of total leukocytes before start of treatment NA 148 OBSERVATIONAL 2 years NCT02302326 Physiopathology of polycystic ovary syndrome https://clinicaltrials.gov/study/NCT02302326 COMPLETED Polycystic ovary syndrome DRUG: Metformin|DIETARY_SUPPLEMENT: Myo-inositol + folic acid NA 50 INTERVENTIONAL 11 months NCT03722979 Extracorporeal circulation in humans https://clinicaltrials.gov/study/NCT03722979 UNKNOWN Cardiac surgery PROCEDURE: Cardiac surgery NA 53 INTERVENTIONAL 7 months NCT03331432 Vascular function https://clinicaltrials.gov/study/NCT03331432 COMPLETED Type 2 diabetes mellitus DIETARY_SUPPLEMENT: Tauroursodeoxycholic acid|DIETARY_SUPPLEMENT: Placebo NA 8 INTERVENTIONAL 2 years NCT04041232 Achromatopsia https://clinicaltrials.gov/study/NCT04041232 NOT_YET_RECRUITING ACHROMATOPSIA 7|Achromatopsia DRUG: PBA EARLY_PHASE1 2 INTERVENTIONAL 2 days NCT01877551 Insulin resistance https://clinicaltrials.gov/study/NCT01877551 COMPLETED HIV related insulin resistance|Protease inhibitor related insulin resistance|Endoplasmic reticulum stress DRUG: Tauroursodeoxycholic acid|OTHER: Placebo tablet NA 27 INTERVENTIONAL 9 months NCT02218619 Type 1 diabetes https://clinicaltrials.gov/study/NCT02218619 UNKNOWN Type 1 diabetes DRUG: Tauroursodeoxycholic Acid (TUDCA)|DRUG: Sugar Pill (placebo) PHASE2 20 INTERVENTIONAL 2 months NCT02841553 Wolfram syndrome https://clinicaltrials.gov/study/NCT02841553 RECRUITING Wolfram syndrome|Diabetes mellitus|Optic nerve atrophy|Deafness|Diabetes insipidus|Ataxia NA 300 OBSERVATIONAL 9 months NCT03798977 Melanoma https://clinicaltrials.gov/study/NCT03798977 COMPLETED Melanoma NA 20 OBSERVATIONAL 3 years NCT03462940 Type 2 DM https://clinicaltrials.gov/study/NCT03462940 TERMINATED Diabetes mellitus, type 2|Insulin response|Endothelial dysfunction DIETARY_SUPPLEMENT: tauroursodeoxycholic acid NA 2 INTERVENTIONAL 10 months NCT02829268 Wolfram syndrome https://clinicaltrials.gov/study/NCT02829268 COMPLETED Wolfram syndrome|Diabetes mellitus|Optic nerve atrophy|Ataxia DRUG: dantrolene sodium PHASE1|PHASE2 21 INTERVENTIONAL 2 months NCT06660784 Diaphragm dysfunction https://clinicaltrials.gov/study/NCT06660784 ACTIVE_NOT_RECRUITING Tracheal intubation|Extracorporeal membrane oxygenation|Nitric oxide|Ventilator-induced diaphragmatic dysfunction DRUG: nitric oxide NA 80 OBSERVATIONAL 2 years NCT01056497 Impairment of glucose-stimulated insulin secretion https://clinicaltrials.gov/study/NCT01056497 COMPLETED Type 2 diabetes|Prediabetes DRUG: alpha lipoic acid PHASE4 15 INTERVENTIONAL 4 months NCT04041232 PBA use for treatment https://clinicaltrials.gov/study/NCT04041232 NOT_YET_RECRUITING ACHROMATOPSIA 7|Achromatopsia DRUG: PBA EARLY_PHASE1 2 INTERVENTIONAL 3 days NCT04122586 Intestinal mucosal barrier of IBS-D https://clinicaltrials.gov/study/NCT04122586 UNKNOWN IBS (irritable bowel syndrome) DRUG: Tongxieyaofang (granule) NA 60 INTERVENTIONAL 3 years NCT05027594 Multiple myeloma https://clinicaltrials.gov/study/NCT05027594 TERMINATED Multiple myeloma DRUG: NMS-03597812|DRUG: NMS-03597812 + dexamethasone PHASE1 5 INTERVENTIONAL 2 years Clinical trials of targeted ER stress TUDCA and PBA are common modulators of the ER stress pathway. These two agents were used in a clinical trial ( NCT00771901 ) to induce a decrease in the ER stress response to improve insulin action and hepatic lipid metabolism in obese patients with IR and hyperlipidemia. 480 Researchers have conducted a 4-week randomized controlled trial in obese subjects to assess adipose tissue insulin signaling, ER stress, and inflammation by evaluating adipose tissue biopsy tissue both in vivo and ex vivo. TUDCA was administered at 1750 mg per day for four weeks: seven capsules per day, two for breakfast, two for lunch, and three for dinner. 20 grams of PBA per day for four weeks. The results of the trial after four weeks revealed that treatment with TUDCA increased insulin sensitivity in the liver and muscle by approximately 30%, but no effects of TUDCA on adipose tissue insulin sensitivity or ER stress were detected. Although treatment of obese mice with TUDCA reduced ER stress in the liver and adipose tissue, the association may not be significant in the population. In addition, liver sensitivity to insulin and VLDL-triglyceride (TG) concentrations were increased in PBA-treated patients. Furthermore, TUDCA was explored in a clinical trial ( NCT01877551 ) to improve insulin action in HIV-infected patients. Researchers improved insulin sensitivity in subjects with protease inhibitor-associated IR by determining whether and how TUDCA improves insulin sensitivity through ER stress. Body composition analysis was performed on 48 HIV-infected, IR/prediabetic subjects via a DEXA machine to measure liver fat via MRI. Patients will take 1.75 grams of TUDCA once daily for 30 days. The control group will take the same placebo tablets as the treatment group but without TUDCA. Once a day for 30 days. Each subject’s fat content, relative amount of fat in the liver, and liver function will be measured daily before and after treatment with TUDCA or placebo. The results revealed a significant reduction in glucose uptake and the relative amount of fat in the liver. Dantrolene sodium is an acetylenic urea derivative skeletal muscle relaxant whose core target of action is ryanodine receptors (RyRs), which are located in the ER membrane and are responsible for regulating the release of calcium ions from the ER to the cytoplasm. 481 It was used to treat Wolfram syndrome in a recent clinical trial ( NCT02829268 ). 482 Wolfram syndrome is a rare, autosomal recessive disorder caused by mutations in the WFS1 gene. The protein encoded by WFS1 is localized in the ER membrane and is involved in the regulation of ER calcium homeostasis and the stress response. WFS1 dysfunction leads to depletion of the ER calcium pool, triggering persistent ER stress and ultimately leading to the apoptosis of pancreatic β-cells and neurons. Studies have shown that the activation of calcium-dependent proteases accelerates cell death in WFS1-deficient cells and that ER calcium imbalance is a central mechanism in this process. 483 The trial included a 56-day screening period, a 6-month treatment period (with an optional extension period of up to 24 months), and a 4-week safety follow-up period. By blocking RyR channels, dantrolene sodium reduces the passive leakage of calcium from the ER and increases storage capacity. Preclinical studies have shown that in WFS1-deficient mice and induced pluripotent stem cell (iPSC) models, dantrolene sodium significantly increases intra-ER calcium levels and decreases calpain activity, thereby protecting cells from apoptosis. To test the therapeutic effect of dantrolene sodium, researchers determined the effect of dantrolene sodium on remaining beta-cell functions via a mixed-meal tolerance test and monitored baseline C-peptide levels, blood glucose levels, proinsulin/C-peptide ratios, hemoglobin A1c levels, and urine glucose levels. In addition, the researchers assessed the effect of dantrolene sodium on visual functions through LogMar scores and questionnaires and evaluated the efficacy of dantrolene sodium on neurological functions via the Wolfram Unified Rating Scale (WURS) and standard neurological assessments. The results revealed no significant improvement in beta-cell function at the end of the six-month treatment, but there was a significant correlation between baseline beta-cell function and changes in beta-cell reactivity. Furthermore, tolerance ranges of 0.5 mg/kg/d to 2 mg/kg/d for oral dantrolene sodium in children and 50 mg/d to 100 mg/d for oral dantrolene sodium in adults were determined. Overall, Dantrolene sodium was well tolerated in patients with Wolfram syndrome. An analysis of the ClinicalTrials.gov database revealed that these studies focused mainly on cancer treatment and metabolic diseases, aiming to explore how to improve the prognosis of diseases and patients’ quality of life by modulating the ER stress response. As research into the molecular mechanisms of ER stress continues to evolve, the need for innovative therapeutic approaches has become increasingly apparent, prompting scientists to explore targeted interventions. Emerging drugs aim to enhance the protective mechanisms of cells against ER stress or selectively eliminate damaged cells, offering a promising avenue for treating conditions previously deemed difficult to manage. These advancements represent a significant shift in the therapeutic landscape, highlighting the potential for tailored treatments that address the underlying causes of ER stress-related diseases. A cancer vaccine uses tumor antigens to induce specific antitumor effects through active immunity, stimulating the immune system to treat or prevent tumor recurrence as a form of active immunotherapy. It amplifies the responsiveness of tumor-specific T cells, usually through active immunity, and has long been regarded as a vital tool for effective cancer immunotherapy. 484 In 2010, Boozari et al. reported that PIs disrupted the UPR and enhanced ER stress-induced apoptosis, leading to the proposal of virotherapy as an antitumor vaccine. 485 The ideal in situ vaccine strategy induces tumor ICD, effectively activating an immune response against antigens from dead or dying tumor cells. Recently, Liu et al. developed Par-ICG-Lipo, a cancer vaccine, by loading indocyanine green (ICG) into liposomes and modifying its surface with a peptide targeting the ER with pardaxin. 40 Par-ICG-Lipo-induced ER-targeted photodynamic therapy (PDT) promotes tumor antigen release in vivo, stimulating a strong antitumor immune response. 486 Specifically, significant increases in both CD8+ and CD4+ T cells suggest that in situ tumor vaccines effectively promote DC maturation and immune system activation. While both ICG-Lipo and Par-ICG-Lipo showed antitumor effects under laser irradiation, Par-ICG-Lipo was more potent. This innovative in situ tumor vaccine represents a clinically viable approach for cancer treatment. SA-Cbl, another ICD inducer, is also being explored for cancer vaccine development. 487 It was developed by conjugating chloramphenicol (Cbl) with salicylaldehyde (SA), which precisely targets the ER-activated UPR pathway and promotes DC maturation. These findings indicate that SA-Cbl has superior anticancer immune effects compared with those of standard chemotherapies, such as doxorubicin. The latest cancer vaccines targeting ER stress, called photoactivatable TLR7/8 antagonists (PNAs), rely on PDT-generated ROS to induce ICD, resulting in tumor antigens and, finally, the activation of T lymphocytes for tumor killing (Table 2 ). 488 This vaccine has shown efficacy in several tumor models, especially in in situ breast cancer models. Treatment with PNA and infrared light reduced the primary tumor size in cured mice. Recent studies have highlighted oncolytic viruses such as swine pseudorabies virus vaccines, which induce eIF2α expression in tumor cells, activating ER stress to kill cancer cells (Table 2 ). 489 Similarly, tumor-derived extracellular vesicles are being explored as cancer vaccines. Extracellular vesicles can induce ER stress in tumor cells, leading to the effective activation of DCs and the enhancement of antitumor immune responses. 490 The addition of immune adjuvants may enhance these novel tumor vaccines. Despite their development, cancer vaccines are still in the early stages compared with conventional treatments. Their safety requires further validation before widespread clinical use can be achieved. In recent years, fluorescent probes have been identified as novel strategies for imaging tumors and guiding therapies. Fluorescent probes that target the ER can not only identify the type of ER stress-producing cells but also quantify the dynamics of the ER stress response. ER-BnXPI, an ER-targeted near-infrared fluorescent probe, showed excellent subcellular localization to the ER and successfully distinguished tumor tissue from paracancerous tissue. 491 Similarly, the ER-localized response molecules (ERMs) developed by Fujisawa et al. achieved spontaneous localization in the ER of cells and even selectively labeled ER-associated proteins via affinity and imaging tags, which supported the quantitative analysis of the extent of ER-associated protein-induced ER stress responses. 492 Wang et al. synthesized a unique near-infrared fluorophore, IR-34, which can selectively trigger ER stress in tumors. 493 Experiments have shown that IR-34 can significantly inhibit tumor growth and recurrence without significant toxicity. TPA-DHPy, a state-of-the-art photoactivatable fluorescent probe, can be absorbed by cancer cells and gradually light up lipid droplets and the ER during photoactivation. In addition, it can further disrupt the function of the ER under prolonged irradiation and significantly inhibit tumor growth through photodynamic therapy. 494 In addition to fluorescent probe technology, Man et al. combined it with gene coding technology to synthesize CLP-TMR, which can reconstruct the molecular location of ER morphology via direct stochastic optical reconstruction microscopy imaging. 495 These studies provide useful insights for the design of a new generation of therapeutic agents targeting ER stress, which could help realize imaging-guided precision cancer therapy. The development of nanomedicine platforms offers the possibility to address the shortcomings of conventional drugs, but developing nanomedicines and thus achieving efficient treatment of tumors has been a challenge. Grandhi et al. synthesized a novel aminoglycoside-derived hydrogel, Amikagel, which can promote dormancy in bladder cancer cells (Table 2 ). It induces ER stress by inhibiting targets in the cellular protein production machinery, and in addition, nanoparticle-mediated calcium delivery significantly accelerates ER stress-mediated death in the three-dimensional dormant TME. 496 Recently, ER and mitochondria dual-targeting nanoparticles (EMT-NPs) have been designed as alternatives to conventional drugs for cancer treatment (Table 2 ). 497 EMT-NPs synergistically induce ER stress and mitochondrial dysfunction in tumor cells and induce calcium ion overload in mitochondria by increasing the expression of ER stress-related proteins (IRE1 and CHOP), which further exacerbates apoptosis in cancer cells. The intelligent redox-responsive generation 3 (G3) poly(amidoamine) dendrimer nanogels (NGs) loaded with gold nanoparticles (Au NPs) and the chemotherapeutic drug toyocamycin (Au/Toy@G3 NGs) developed by Zhang et al. represent the latest nanomedicine targeting ER stress (Table 2 ). 498 Toy released from Au/Toy@G3 NGs promotes cancer apoptosis via ER stress and causes immunogenic cell death in mature DCs. In experiments on mouse models of pancreatic tumors, the combination of Au/Toy@G3 NGs with ultrasound-targeted microbubble destruction and anti-PD-L1 had the best tumor suppression effect in combination therapy, enabling effective chemoimmunotherapy. In conclusion, these nanogel strategies with targeted ER stress-associated functions offer unlimited possibilities for cancer therapeutics in precision nanomedicine.

The endoplasmic reticulum (ER), an organelle in most eukaryotic cells, is the foundation for synthesizing several essential substances, including proteins, lipids, and sugars, in addition to nucleic acids. 1 Furthermore, the ER consists of a series of lamellar vesicles and tubular lumens, forming a continuous reticular system that links the nucleus, cytoplasm, and cell membrane, thereby facilitating the transport of substances. 2 Almost all proteins originate in the cytoplasmic matrix and are shortly thereafter translocated to the ER. Specifically, most secreted and transmembrane proteins, including those involved in synthesis, folding, and maturation, begin traveling within the ER lumen. Once appropriately modified, these proteins are either transported to their specific destinations within the cell or released outside through the cell membrane. 3 However, the process of generating proteins does not necessarily proceed in the right direction, and a variety of intrinsic and extrinsic factors may induce ER stress, which is characterized by excessive accumulation of misfolded or unfolded proteins as well as dysregulation of sterol and lipid levels. 4 Mild ER stress can be restored to protein homeostasis by some intracellular processing capacity. Nevertheless, if stress persists beyond the adaptive capacity of the cell, ER stress will activate the unfolded protein response (UPR). This adaptive signaling pathway reduces the burden on unfolded or misfolded proteins, thereby restoring the balance of proteins. 5 When ER stress is extremely severe or persists for too long, it exceeds the adaptive capacity of the cell and may initiate an apoptotic program. 6 Although ER stress usually triggers the UPR, whether the UPR promotes cellular adaptation back to normal or initiates cell death depends on various factors. Researchers have used ER stress in clinical applications to treat numerous types of diseases because of an understanding of its mechanisms. Growing evidence suggests that the ER stress response can influence the cellular phenotypes critical for cancer onset, progression, and treatment. 7 On the one hand, if the ER stress response that persists in tumor cells is targeted to be induced, leading to their death, this would help prevent cancer progression. 8 On the other hand, inhibiting UPR signaling to enhance antitumor immune responses could make the ER stress response system a potential target for cancer immunotherapy. 9 Cardiovascular diseases are often affected by the accumulation of unfolded or misfolded proteins in the ER, leading to cellular damage that causes cardiovascular dysfunction. 10 Cardiovascular disease is triggered by an imbalance in ER homeostasis, which in turn disrupts the function of the secretory pathway, leading to exacerbation of the ER stress response. ER stress is a critical contributor to the pathogenesis of neurodegenerative diseases, as it disrupts protein folding and impairs neuronal survival. 11 This stress activates the UPR, which, when overwhelmed, leads to neuronal apoptosis and neuroinflammation. The resulting cellular dysfunction is closely associated with cognitive decline and neurodegeneration. ER stress plays a pivotal role in the dysregulation of lipid and glucose homeostasis in metabolic diseases, leading to insulin resistance (IR) and metabolic dysfunction. 12 The accumulation of misfolded proteins within the ER triggers the UPR, further exacerbating metabolic disturbances. This interplay contributes to the progression of various metabolic diseases and associated complications. ER stress is also implicated in the pathogenesis of autoimmune diseases, where it can increase the activation of immune cells and promote the secretion of proinflammatory cytokines. 13 The UPR is activated in response to ER stress, increasing antigen presentation and autoimmune reactivity. This process ultimately results in tissue damage and the exacerbation of autoimmune responses. Therefore, given the role of ER stress in disease pathogenesis, understanding its complex mechanisms in cells of various tissues is important for studying disease pathogenesis and therapeutic strategies. This review systematically focuses on characterizing ER stress in multiple disease states and explores therapeutic strategies to target ER stress. First, we describe the major research findings in the relevant fields. Next, ER stress-related regulators and their functional mechanisms are described in detail. We subsequently investigated the role of ER stress in five typical disease categories, namely, cancer, cardiovascular disease, neurodegenerative disease, metabolic disease, and autoimmune disease. In addition, we emphasize the feasibility of targeting ER stress as a therapeutic agent and the current status of clinical trials. Finally, we profile several novel drugs for treating ER stress and suggest possible gaps in the current research. We believe that this review will deepen our understanding of the mechanisms of ER stress and elucidate its regulatory functions in human cells during disease progression, thereby improving the efficacy of therapies targeting ER stress.