The Estrogen-Autophagy Axis: Insights into Cytoprotection and Therapeutic Potential in Cancer and Infection.

Over the past few decades, there has been a growing body of research exploring the relationship between estrogen signaling and autophagy [ 15 , 16 ]. Most synthetic modulators that influence estrogen’s effects, including ligands for ESRs, were originally developed for the clinical treatment of ESR-positive breast cancers [ 17 ]. However, the impact of these estrogen regulators extends beyond cancer, affecting various tissues such as the brain, bone, visceral fat, skin, lymphatic system, adrenal medulla, oral cavity, and eyes. This suggests that the link between estrogen and autophagy may play a role in developing treatments for a range of diseases, not just cancers [ 14 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 ]. Autophagy is a dynamic process that involves the coordinated action of numerous proteins, which serve as biomarkers, such as MAP1LC3 (microtubule-associated protein 1 light chain 3) and those related to autophagy flux (the MAP1LC3-II:MAP1LC3-I ratio), as well as autophagy substrates including SQSTM1 (sequestosome 1) and the morphological features of autophagosomes and autolysosomes [ 41 ]. Additionally, BECN1 (beclin 1) is a crucial regulator of autophagy during the nucleation phase. However, variations in its expression levels appear to correlate more closely with autophagy regulation than with morphological changes or the expression patterns of autophagy biomarkers such as MAP1LC3. As summarized in Table S1 , E2 induces the degradation of ESR1 in MCF-7 cells and increases the number of autophagosomes [ 18 ]. Furthermore, E2 upregulate BECN1 via ESR2 in MDA-MB-231 cells [ 19 ], promote autophagosome formation and apoptosis in renal cell carcinoma [ 28 ], and enhance the expression of MAP1LC3-II in pulmonary artery endothelial cells in a rat model of hypoxia, indicating a protective effect against hypoxia-induced pulmonary hypertension [ 20 , 21 ]. Additionally, E2 stimulates autophagy by upregulating BECN1 and enhancing autophagy flux, which effectively suppresses apoptosis in rat nucleus pulposus cells and osteocytes, as well as human osteoblasts and retinal pigment epithelial cells [ 22 , 23 , 24 , 26 , 29 ]. E2 also increases the ratio of autolysosomes to autophagosomes, demonstrating a significant therapeutic effect in a rat model of Parkinson disease [ 27 ]. It also inhibits the expression of certain autophagy-related proteins in response to various conditions, including endometriosis, hypoxia, ischemia, lipopolysaccharides, spinal cord injury, NaAsO 2 exposure, and ovariectomy [ 32 , 36 , 38 , 39 ]. Specific modulators have been developed to target the activities of ESR1, ESR2, and GPER1. These include ESR1 antagonists such as tamoxifen, raloxifene, and fulvestrant [ 17 ]. Both fulvestrant and resveratrol promote autophagy while limiting the upregulation of autophagy induced by rapamycin or H 2 O 2 [ 14 , 42 ]. G1, a GPER1 agonist, inhibits excessive autophagy induced by angiotensin II or glutamate [ 43 , 44 ]. Notably, the activities of fulvestrant and G1 are similar to those of E2, as all three act as agonists for GPER1, although some also serve as antagonists for ESR1 ( Figure 1 ). These findings indicate that estrogen regulation has dual effects on autophagy, complicating the determination of whether the type of ligand affects autophagy regulation. To date, several estrogen antagonists have been synthesized, including the ESR1-selective antagonist 1,3-bis(4-hydroxyphenyl)-4-methyl-5-(4-[2-piperidinylethoxy]phenol)-1H-pyrazole dihydrochloride (MPP), the ESR2-selective antagonist 4-(2-phenyl-5,7-bis[trifluoromethyl]pyrazolo[1,5-a]pyrimidin-3-yl)phenol (PHTPP), and the GPER1 antagonist G15 [ 45 , 46 ]. Both MPP and PHTPP inhibit autophagy by suppressing autophagy flux [ 46 ], whereas G15 blocks G1’s action, resulting in the accumulation of MAP1LC3B-II and autophagosomes, similar to the effect of pre-treatment with chloroquine, which increases increase autophagosome accumulation [ 13 , 45 , 47 ]. Furthermore, silencing ESR1 mRNA using small interfering RNA also inhibits autophagy [ 43 ]. Together, these findings suggest that ESR ligands regulate autophagy and that the autophagy induced by estrogen can be blocked with antagonists ( Figure 1 , Table S2 ) [ 13 , 14 , 42 , 43 , 44 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 ]. ESR1, ESR2, and GPER1 exhibit distinct patterns of distribution and expression in both normal physiological and disease conditions. As illustrated in Figure 2 , GPER1 and ESR2 are more broadly distributed among human cell types compared to ESR1. These differences in expression patterns have been identified as potential biomarkers for assessing the risk of malignant cancers, including those of the breast, endometrium, and ovary [ 72 , 73 , 74 ]. The lymphatic system serves as a common pathway for the spread of breast cancer cells, occurring at a frequency comparable to hematogenous (i.e., blood borne) metastasis. Approximately 75% of primary breast cancers are ESR1-positive, with lymph nodes being the primary metastatic sites for these ESR1-positive breast cancer cells. Notably, the presence of ESR1-positive follicular dendritic cells in lymph nodes has been recognized as a novel prognostic marker for breast cancer, aiding in therapeutic decision-making [ 63 ]. For instance, triple-negative breast cancer, which lacks ESR1 expression, has the poorest prognosis among the five molecular subtypes of breast cancer. This is attributed to a high mitotic rate, extensive lymphocyte infiltration, advanced tumor grade, and larger tumor size. All three estrogen receptors—ESR1, ESR2, and GPER1—are expressed in the pituitary gland [ 75 ] and play roles in neuronal-mediated contractions of the ileal tissues in females. In contrast, only ESR1 is found in the ileal tissues of males [ 76 ]. This distribution may contribute to the differing prevalence of gastrointestinal cancer and non-erosive reflux disease between genders, with such conditions being more common in men, whereas functional gastrointestinal disorders are frequently observed in women [ 77 , 78 ]. Additionally, all three ESRs have been identified in the human bladder [ 79 ]. While both ESR1 and ESR2 (but not GPER1) protect the human bladder and kidney from Escherichia coli infections, they also play roles in the carcinogenesis, progression, and chemosensitivity of bladder cancer [ 80 , 81 ]. Furthermore, ESR1-mediated estrogen signaling is crucial for effective liver regeneration following partial hepatectomy [ 82 ]. ESR1 significantly contributes to metabolic regulation in skeletal muscle but is not essential for regulating insulin sensitivity or mitochondrial function [ 83 ]. In contrast, ESR2 is involved in a sex-specific regulatory mechanism that governs muscle growth and regeneration in female mice [ 84 ]. The antifibrogenic effects of estrogen are primarily mediated by ESR2 rather than ESR1 or GPER1 in rats [ 85 ]. Notably, ESR2 is the predominant subtype expressed in colon tissues, and E2 may protect against acute colitis through ESR2 activation. An upregulation of ESR2 expression in colon cancer is associated with improved survival outcomes [ 86 ]. In the normal thyroid gland, a limited number of follicular cells express ESR1, whereas both follicular and C cells express ESR2, even in the developing fetus [ 87 ]. ESR2 is highly expressed in type I and II pneumocytes as well as bronchiolar epithelial cells, whereas ESR1 is undetectable in the adult lung [ 88 ]. Furthermore, ESR2 appears to be the predominant estrogen receptor subtype in lung cancer [ 89 ], the oral epithelium, and salivary glands [ 90 ]. While both ESR1 and ESR2 are present in gastric cancer [ 86 ], expression of ESR2 in non-cancerous tissues is significantly higher in female than in male rats. ESR1 is found in only a small percentage of older males with oral squamous cell carcinoma, whereas young females generally do not express ESR1 or the progesterone receptor [ 91 ]; however, ESR2 is predominantly expressed in tissue samples from patients with oral cancer [ 91 ]. GPER1 plays neuroprotective roles and is associated with vascular pathology in various tissues [ 92 ]. This receptor induces pleiotropic effects in metabolically active tissues, including the pancreas, adipose tissue, liver, and skeletal muscle. Research has demonstrated that GPER1 is involved in regulating body weight, feeding behavior, inflammation, and glucose and lipid homeostasis [ 93 ]. GPER1 is expressed in the rat pituitary gland, particularly in lactotropic cells [ 94 ], and can reduce autophagy in retinal astrocytes under hyperoxic conditions [ 95 ]. Moreover, GPER1 expression is upregulated during the differentiation of 3T3-L1 preadipocytes into adipocytes, with higher levels observed in female than male mice [ 93 ]. In the liver, GPER1 modulates lipid metabolism, lowers circulating lipid levels, and reduces inflammation, as supported by several preclinical and clinical studies. A hypofunctional genetic variant of GPER1 is linked to elevated plasma low-density lipoprotein cholesterol levels [ 96 ]. In uterine circulation, GPER1 triggers a vasoactive response, primarily through the nitric oxide–cyclic guanosine monophosphate signaling pathway in uterine arteries, a mechanism that may be altered during pregnancy [ 97 ]. GPER1 is recognized as the primary mediator of estrogen’s effects in the prostate, where its signaling contributes to E2-dependent activation of endothelial nitric oxide production and subsequent vasodilation. It also promotes sodium excretion via an EDN1 (endothelin 1)-dependent pathway in female, but not male, rats, thereby enhancing renal vascular function against ischemia-reperfusion injury. Additionally, GPER1 is present in the skin, which serves as a barrier against microbial pathogens. It is located in the membranes of endothelial cells and various skin cells, including keratinocytes, melanocytes, and dermal fibroblasts [ 98 ]. GPER1 activation mitigates pathogenesis in a mouse model of Staphylococcus aureus skin infections, reinforcing the role of estrogen in supporting innate immunity against infectious diseases via GPER1. GPER1 is expressed in various cancers, with higher levels of GPER expression linked to tumor development in some female reproductive system neoplasms and associated with poor prognosis [ 99 ]. Furthermore, GPER1 is found in the majority of mantle cell lymphoma cases, suggesting that therapies targeting GPER1 could benefit these patients [ 99 ]. Even at low expression levels, GPER1 has been independently associated with lymph node metastasis in papillary thyroid carcinoma [ 100 , 101 ]. Notably, GPER1 expression is higher in lung tumors compared to normal lung tissues [ 102 ]. However, it is inversely associated with lymph node metastasis, high-grade tumors, and FN1 (fibronectin 1) expression, while positively correlated with favorable outcomes in patients with triple-negative breast cancer [ 103 ]. Downregulation of GPER1 has been linked to poor prognosis in gastric cancer, and it may function as a tumor suppressor by regulating epithelial–mesenchymal transition in this context [ 104 ]. GPER1 activation results in the depletion of MYC/c-Myc, inhibition of tumor proliferation, and enhanced immune recognition by tumor cells [ 105 ]. Beyond tissue distribution, the intracellular localization of ESRs also varies among different cell types [ 106 , 107 , 108 , 109 ] and is closely related to physiological states such as estrogen status. This localization plays a critical role in mediating estrogen signaling and autophagy. Autophagy is a dynamic process that involves the coordination of various proteins and can be divided into four key stages: (1) induction, (2) phagophore nucleation and expansion, (3) autophagosome maturation and fusion with endosomes and/or lysosomes, and (4) cargo degradation and recycling. MTOR (mechanistic target of rapamycin kinase) plays a crucial role in regulating autophagy by inhibiting its initiation. When stimulated by estrogen, ESR1 binds to RPTOR/Raptor, a regulatory protein of MTOR complex 1 [ 110 ]. This interaction leads to the phosphorylation of Ser104/106 on ESR1, promoting the transcription of target genes associated with ESR1 [ 110 , 111 ]. Beyond this direct interaction, the regulation of autophagy-related genes by estrogen relies heavily on transcription factors downstream of ESRs. As shown in Figure 3 , upon estrogen stimulation, the expression of many autophagy-related genes is influenced by multiple transcription factors, each regulated by two or three ESRs. Complex interactions can occur among different receptors and transcription factors, as well as between transcription factors and autophagy-related genes. Notable examples include ESR1, ESR2, TFEB (transcription factor EB), ZKSCAN3 (zinc finger with KRAB and SCAN domain 3), and the tumor suppressor TP53 (tumor protein p53), along with MDM2 (MDM2 proto-oncogene) [ 105 , 112 , 113 ]. In addition to the transcription factors previously discussed, estrogen (E2) regulates the expression of various autophagy-related proteins through microRNAs downstream of ESRs ( Table S3 ) [ 111 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 , 147 , 148 , 149 , 150 , 151 , 152 , 153 , 154 , 155 , 156 , 157 , 158 , 159 , 160 , 161 , 162 , 163 , 164 , 165 , 166 , 167 , 168 , 169 , 170 , 171 , 172 , 173 , 174 , 175 , 176 , 177 , 178 , 179 , 180 , 181 , 182 , 183 , 184 , 185 , 186 , 187 , 188 , 189 ]. For instance, RB1CC1 (RB1 inducible coiled-coil 1), a nuclear DNA-binding protein that plays a crucial role in autophagy induction, is suppressed by MIR10A-5p (microRNA 10a) [ 171 ]. Notably, MIR10A expression can be upregulated by estrogen via ESR2 [ 173 ]. Similarly, MIR17 suppresses the expression of ATG7 (autophagy-related 7) in human glioblastoma T98G cells [ 187 ]. In C2C12 myoblasts, MIR20A can inhibit ULK1 (unc-51 like autophagy activating kinase 1) expression [ 174 ]. Both MIR17 and MIR20A are upregulated by E2 in MCF-7 cells through ESR1 signaling [ 175 ]. Moreover, MIR21 has been identified as a regulator of BCL2 (BCL2 apoptosis regulator) mRNA in rat and human beta cells [ 180 ]. However, the impact of estrogen on MIR21 expression varies with experimental conditions and cell lines; for example, E2 inhibits MIR21 through ESR1 in HepG2 cells [ 181 ], while a selective agonist of ESR2 upregulates it in MCF-7 cells [ 178 ]. Additionally, both ATG12 and BECN1 are negatively regulated by STAT1 (signal transducer and activator of transcription 1) [ 184 ], which is also targeted by MIR21 [ 131 ]. UCP2 (uncoupling protein 2), an inner mitochondrial membrane protein, can promote autophagy and endocrine resistance in breast cancer via the ROS1 (ROS proto-oncogene 1, receptor tyrosine kinase)–AKT1 (AKT serine/threonine kinase 1)–MTOR signaling pathway [ 48 ]. Estrogen treatment suppresses Mir214 in ovariectomized mice and can directly inhibit UCP2 expression [ 176 , 190 , 191 ]. HOTAIR (HOX transcript antisense RNA) is a long non-coding RNA located within the homeobox C gene cluster. E2 induces HOTAIR expression by suppressing MIR148A through GPER1 [ 183 ]. HOTAIR has been implicated in regulating autophagy, influencing both cisplatin resistance and sensitivity to radiotherapy in various cancers [ 184 , 186 , 192 ]. In hepatocellular carcinoma, HOTAIR promotes autophagy by inducing the expression of ATG3 and ATG7 [ 186 , 188 , 193 ]. The transcription of HOTAIR upregulates ATG3 and ATG7, likely through an indirect competitive endogenous RNA mechanism, with sponging microRNAs contributing to the suppression of these genes [ 194 ]. Additionally, HOTAIR acts as a sponge for MIR138-5p , preventing its interaction with EZH2 (enhancer of zeste 2 polycomb repressive complex 2 subunit) and SIRT1 (sirtuin 1), thus enhancing the resistance of ovarian cancer cells to cisplatin-based chemotherapy [ 195 ]. In cholangiocarcinoma, HOTAIR suppresses autophagy by modulating the MIR204-5p –HMGB1 (high mobility group box 1) axis [ 182 ], while it regulates autophagy through the MIR20B - 5p –ATG7 pathway in hepatic ischemia-reperfusion injury [ 196 ]. Furthermore, HOTAIR competes with MIR17-5p to regulate BECN1 expression [ 184 , 185 , 186 , 188 , 192 , 193 , 194 , 195 , 196 ] and to induce phosphorylation of SNAP23 (synaptosome-associated protein 23) via MTOR signaling [ 197 ]. In breast cancer, HOTAIR mediates autophagy progression through interactions matrix metallopeptidases, which are critical for cancer invasion; CTNNB1/β-catenin (catenin beta 1) may play a significant role in this process [ 198 ]. In a mouse model of Parkinson’s disease, HOTAIR drives autophagy in midbrain dopaminergic neurons by enhancing NPTX2 (neuronal pentraxin 2) expression through binding to Mir221-3p [ 189 ]. Histone acetylation and methylation play crucial roles in regulating gene transcription, acting as switches that affect overall chromatin structure. These modifications are likely involved in estrogen-dependent signaling pathways across various tissues in both normal and pathological states ( Figure 4 ). Notably, cholesterol derivatives induce the dephosphorylation of HDAC1 (histone deacetylase 1), leading to the upregulation of autophagy [ 1 ]. Furthermore, suberoylanilide hydroxamic acid significantly inhibits the activities of HDAC1, HDAC2, and HDAC4, while downregulating GPER1 in a concentration-dependent manner [ 199 ]. SIRT1, an essential deacetylase, facilitates chromosomal condensation by mediating the loading of histone H1 and the condensin I complex onto chromosomes [ 200 ]. This process is critical in regulating the transcription of genes associated with various diseases. For instance, SIRT1 inhibits the puberty-activating gene Kiss1 (KiSS-1 metastasis suppressor) by modulating the chromatin state at its promoter in KISS1/kisspeptin-neurokinin B-dynorphin neurons [ 201 ]. A deficiency in SIRT1 can lead to chromosomal instability and tumor progression. Additionally, estrogen upregulates SIRT1 expression through GPER1, subsequently activating the oncogenic EGFR (epidermal growth factor receptor) signaling pathway, which helps prevent apoptosis in human breast cancer cells, both in vitro and in vivo [ 202 ]. Importantly, SIRT1 deacetylates both histone and non-histone proteins and regulates estrogen biosynthesis by binding to multiple tissue-specific promoters, thereby enhancing the transcription of CYP19A1 (cytochrome P450 family 19 subfamily A member 1), which is also a target of SIRT1-mediated deacetylation [ 203 , 204 ]. Known histone targets of SIRT1 include H1 (Lys 26), H3 (Lys 9, Lys 19, and Lys 79), and H4 (Lys 8 and Lys 16) [ 200 ]. Notably, acetylation of histone H4 at Lys 16 serves as a primary substrate for SIRT1, influencing chromatin accessibility [ 113 ]. KAT8 (lysine acetyltransferase 8) primarily acetylates H4K16, along with certain non-histone proteins, and enhances the ESR1 signaling pathway through its acetylase activity in hepatocellular carcinoma [ 205 ]. Histone acetyltransferases (HATs) facilitate the conversion of the chromatin structure to a more relaxed and transcriptionally active state by acetylating specific lysine residues on histone tails [ 206 ]. HATs are pivotal in gene transcription and affect signaling cascades associated with inflammatory diseases, neurodegenerative disorders, and cancers through the acetylation of both histone and non-histone substrates [ 207 , 208 ]. Additionally, HATs have been implicated in promoting viral invasion and replication by interacting with viral proteins, such as the Tat protein of human immunodeficiency virus type 1 and the E1A protein of adenoviruses [ 209 , 210 ]. NOC2L (NOC2-like nucleolar-associated transcriptional repressor), an inhibitor of HATs, also regulates TP53 activity [ 207 ]. GPER1-mediated activation of HATs can lead to hyperacetylation of histones H3K9ac, H3K14ac, and H4K12ac [ 211 ]. In MCF-7 breast cancer cells, acetylated H3K27 promotes the transcription of ESR1 [ 212 ]. SIRT3 (sirtuin 3) functions as a mitochondrial nicotinamide adenine dinucleotide-dependent HDAC that promotes autophagy in lipotoxic hepatocytes via the AMP-activated protein kinase/ULK1 (unc-51 like autophagy activating kinase 1) pathway [ 128 ]. E2 can influence reactive oxygen species levels by activating SIRT3 via ESR2 in human seminoma TCam-2 cells. This mechanism is crucial for estrogen’s protective effects via ESR2 in adult germ cells, a function often lost in advanced tumors due to downregulation of ESR2 [ 129 ]. Moreover, in ovarian cancer, the tri-methylation of Lys4 on histone H3 is associated with ESR2, while levels of phosphorylated MAPK1 (mitogen-activated protein kinase 1)-MAPK3 are elevated through GPER1 activation [ 134 , 213 ]. The SIRT1–ESR1 signaling pathway plays a significant role in mitigating oxidative stress and neuroinflammation, as well as preventing arterial stiffness. This is achieved through enhanced signaling of the MAPK/JNK-NFKB1 (nuclear factor kappa B subunit 1) pathway and the upregulation of NOS3/eNOS (nitric oxide synthase 3) expression in various preclinical models of chronic diseases [ 214 , 215 ].

Estrogen, a hormone with significant physiological effects, is tightly regulated within the body. Cholesterol serves as the precursor for estrogen biosynthesis, and lipids released through autophagy provide a crucial source of cholesterol. Estrogen in the bloodstream can inhibit the release of hormones from glands through a negative feedback loop. Additionally, estrogen influences various histone modifications, transcription factors, and microRNAs that regulate both estrogen biosynthesis and ESRs, creating further negative feedback loops to finely tune estrogen-mediated cellular responses, including autophagy [ 178 , 216 ]. Regarding the fate of ESRs, human cells utilize both the ubiquitin–proteasome system and autophagy pathways for proteolysis. In eukaryotic cells, ESR1 is primarily degraded through the ubiquitin–proteasome system; however, its levels also decrease with autophagosome formation [ 48 ]. This aligns with prior findings on ESR1 degradation via autophagy, highlighting the inhibitory effects of E2 and other GPER1 agonists on cellular autophagy [ 18 ]. Meanwhile, ESR2 localizes to mitochondria, which are significant substrates for autophagy. GPER1 has also been observed at the autophagosome membrane, showing considerable colocalization with MAP1LC3 [ 11 ]. However, it appears that GPER1 may not be a substrate for autophagy, as its expression levels do not decrease with increased autophagy activity [ 13 ], though further research is necessary to confirm this.

Both autophagy promoters and inhibitors have shown anticancer effects in vitro, yet individual responses in clinical trials vary significantly [ 217 , 218 ]. Estrogen plays a crucial role in these differences, influencing cancer treatment outcomes [ 219 , 220 ]. Its relationship with cancer is complex; for instance, while estrogen can delay apoptosis in ESR1-positive breast cancer cells, it may also protect some women against the disease at a circulatory level and induce apoptosis in estrogen-resistant cancers [ 12 , 221 , 222 ]. Similar to anticancer trials on autophagy modulators, several studies have examined the effectiveness of combining estrogen or its antagonist, raloxifene, with autophagy inducers (including rapamycin and everolimus) or inhibitors (such as chloroquine and hydroxychloroquine) alongside anti-infection therapies, including those targeting SARS-CoV-2 [ 223 , 224 , 225 , 226 , 227 , 228 ]. Our discussion highlights that estrogen promotes autophagy through estrogen receptors by regulating autophagy-related proteins via downstream transcription factors, miRNAs, and histone modifications. Consequently, the effects of estrogen on autophagy can vary with estrogen levels and the expression of its receptors. Autophagy also influences estrogen, with cholesterol produced through autophagy serving as a precursor for estrogen synthesis, while excessive autophagy may degrade estrogen receptors. To clarify the interplay between estrogen and autophagy in cancer progression, we propose a new model ( Figure 5 ), aligned with previous models emphasizing autophagy’s role in maintaining intracellular quality control and homeostasis. This model suggests that estrogen primarily enhances autophagy by regulating ESR levels to ensure balanced autophagy and cellular stability, contrasting with earlier views of estrogen’s dual protective effects. In our model, autophagy is closely linked to ESR levels: excessive autophagy correlates with lower ESR levels, while insufficient autophagy is associated with higher levels. Effective anticancer therapies may disrupt the homeostasis of cancer cells while preserving normal cells. For ESR1-positive breast cancers, estrogen antagonism might be necessary due to the connection between insufficient autophagy and elevated ESR levels, while ESR1-negative cancers might respond better to estrogen agonists. Estrogen can upregulate ESR1, ESR2, and GPER1 [ 229 , 230 ], but its levels are tightly regulated by negative feedback loops and can fluctuate due to factors such as age, sex, menstrual cycle, and environmental influences [ 231 , 232 , 233 , 234 , 235 ]. This variability indicates that autophagy is also susceptible to these factors. Our model suggests that ESR levels may serve as indirect indicators of a cell’s autophagic state, although further research is needed. Both autophagy modulators (rapamycin and everolimus) and inhibitors (chloroquine and hydroxychloroquine) have demonstrated anti-infection properties against various pathogens, including SARS-CoV-2 [ 225 , 226 , 227 , 228 ]. Just as there are individual differences in cancer trials, variations also exist in trials involving microbial pathogens. Recent findings suggest that manipulating estrogen’s effects on autophagy could lead to new treatment strategies for various diseases, not just cancer. Notably, estrogen may interfere with treatments for infections and cancer immunotherapy by regulating the autophagy of immune cells, including macrophages as well as T and B lymphocytes [ 63 , 70 , 142 , 151 , 157 ], which also explains, to some extent, individual differences in responses to autophagy modulators in the anti-infection treatment ( Figure 5 B). Overall, our findings indicate a much closer relationship between estrogen and autophagy than previously recognized. This association affects numerous biological processes, aiding in the understanding of disease mechanisms and the development of innovative treatment approaches, and underscores the need for continued research in this area.

Autophagy is a crucial cytoprotective response that helps cells cope with pathological stresses associated with various diseases, including cancer, ischemia, and infections. It plays a vital role in maintaining the intracellular balance of mass and energy necessary for metabolism, growth, development, and immune function. However, while autophagy is protective in healthy cells, it can also promote drug resistance and nutrient deficiency in cancer cells [ 1 , 2 ]. This dual nature makes autophagy an appealing therapeutic target, as it is intricately linked to a range of metabolic diseases, cancers, developmental disorders, aging, and infectious diseases, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [ 3 , 4 ]. Estrogen, a key sex hormone, is instrumental in the development of secondary sexual characteristics in females and also exerts various cytoprotective effects in pre-menopausal women [ 5 , 6 ]. The classic estrogen receptors, namely ESR1 (estrogen receptor 1) and ESR2, along with GPER1 (G protein-coupled estrogen receptor 1), play significant regulatory roles in mediating estrogen’s effects [ 7 , 8 ]. A proposed model suggests that 17β-estradiol (E2) modulates autophagy in cancers to help maintain cellular homeostasis [ 9 ]. For instance, antagonizing estrogen is often necessary during the treatment of estrogen-related cancers, aligning with the principles of endocrine therapy. However, this model does not fully explain why agonists of ESRs can sometimes provide benefits in cancer treatment [ 10 ]. Notably, estrogen to inhibits the proliferation of MDA-MB-231 cells, which are derived from a highly aggressive and poorly differentiated subtype of triple-negative breast cancer [ 11 ]. Additionally, clinical trials have indicated that high doses of estrogen may exhibit antitumor effects in postmenopausal breast cancer patients who are resistant to endocrine therapies [ 12 ]. Furthermore, some estrogen antagonists have been found to inhibit autophagy [ 13 , 14 ]. Estrogen also plays crucial regulatory roles in the immune response, highlighting the importance of the crosstalk between estrogen signaling and autophagy in the onset and progression of cancer. This review summarizes the molecular mechanisms underlying the cytoprotective effects resulting from the interplay between estrogen signaling and autophagy. We explore how various ligands and cell types, including immune cells, influence this relationship in the context of disease. Additionally, we discuss factors affecting estrogen regulation of autophagy, such as ESRs, transcription factors, microRNAs, and histone modifications. Finally, we examine the implications of the estrogen–autophagy axis on cell fate to guide future research directions.