Role of SPRY4 in health and disease.

SPRY4 participates in the occurrence and development of tumors by regulating cellular signaling pathways. The regulatory role of SPRY4 in tumor development is mainly achieved through the following aspects: ①Inhibition of cell proliferation: SPRY4 inhibits tumor cell proliferation by regulating cell proliferation-related signaling pathways, such as the Ras-MAPK and PI3K-Akt pathways ( 12 , 50 , 51 ). ②Cell differentiation: SPRY4 plays an important role in normal cell differentiation processes ( 46 , 52 , 53 ). Additionally, SPRY4 inhibits tumor development by regulating cell differentiation in rhabdomyosarcoma and non-small cell lung cancer ( 29 , 54 ). ③Inhibition of invasion and metastasis: SPRY4 also plays a significant role in regulating tumor cell invasion. It can inhibit tumor cell invasion and metastasis by modulating key factors such as cell adhesion, cytoskeleton, and extracellular matrix degradation. SPRY4 can suppress the activity of matrix metalloproteinase 9, increase the expression of TIMP1 and CD82, and inhibit tumor cell invasion and metastasis ( 29 ). SPRY4 induces macrophage-induced protrusion formation and cytoskeletal changes in undifferentiated thyroid cancer cells, thereby increasing cancer cell invasiveness ( 55 ). SPRY4 overexpression induces remodeling of the actin cytoskeleton and inhibits extracellular matrix proteolysis, thus inhibiting invasion of breast ductal carcinoma cells ( 56 ). ④Regulation of tumor microenvironment: SPRY4 may regulate tumor occurrence by influencing cell-cell interactions and the release of signaling molecules in the tumor microenvironment. SPRY4 may act as a mediator of communication between macrophages and undifferentiated thyroid cancer cells, exerting tumor-suppressive effects ( 55 ). Moreover, as a tumor suppressor, SPRY4 can inhibit angiogenesis and increase vascular permeability in Lewis lung cancer in mice ( 27 ). When the function of SPRY4 is affected by gene mutations, excessive methylation, epigenetic modifications, and mRNA and protein stability, its ability to regulate cellular signaling pathways may be impaired. This can contribute to the occurrence and development of tumors.①Gene mutations: Missense mutations in the coding sequence of the SPRY4 gene generate SPRY4 protein variants (amino acid residue 241 changes from tyrosine to serine). Mutations in the SPRY4 protein inhibit cell migration in osteosarcoma-derived cell lines ( 57 ). Another SPRY4 protein variant is generated when the cytosine at the 701st nucleotide position in the SPRY4 coding sequence mutates to thymine, resulting in threonine-to-methionine substitution at amino acid residue 234. This variant promotes the proliferation of thyroid cancer cells ( 58 ). ②mRNA and protein stability: In non-small cell lung cancer, significantly upregulated KSRP protein promotes rapid decay of SPRY4 mRNA, leading to increased cell proliferation, migration, and invasion, thereby promoting lung cancer development ( 59 ). Additionally, several microRNAs, such as miR-411-5p (rhabdomyosarcoma), miR-411 (non-small cell lung cancer), miR-18a (non-small cell lung cancer), miR-92a (non-small cell lung cancer), miR-1908 (glioma), and miR-181 (breast cancer), downregulate SPRY4 by directly targeting and degrading SPRY4 transcripts in various cancer cells, promoting tumor occurrence and development ( 54 , 60 – 63 ). However, miR-302s act as an oncogene in TGCT by inducing SPRY4 expression, activating the MAPK/ERK pathway, and inhibiting apoptosis through increased survivin expression ( 50 ). In normal monkey kidney cells, E3 ubiquitin ligase SIAH2 leads to a decrease in SPRY4 protein levels, but its effect is relatively minor under the influence of SIAH2 ( 64 ). ③Epigenetic modifications: The expression levels of SPRY4 may be significantly downregulated in certain tumors, possibly due to changes in gene epigenetic modifications. In hepatocellular carcinoma-resistant patients, histone deacetylase 4 (HDAC4) modifies the chromatin configuration within the SPRY4 promoter region, leading to transcriptional inhibition of the SPRY4 gene ( 65 ). CCAT1-mediated histone methylation (H3K9me2 and H3K9me3) may also contribute to decreased expression of SPRY4 in esophageal squamous cell carcinoma, promoting cell growth and migration ( 66 ). ④Excessive methylation: Excessive methylation of the SPRY4 gene promoter region can lead to gene silencing and downregulation of expression, resulting in the loss of its regulatory role in cellular signaling transduction. High methylation in the SPRY4 promoter region has been observed in patients with prostate cancer ( 67 ), colorectal cancer ( 68 ), and familial testicular cancer ( 69 ), leading to transcriptional inactivation of SPRY4 and promoting tumor occurrence and development. In human colorectal cancer tumors, overexpression of UHRF1 upregulates SPRY4 transcriptional activity by regulating 5-hydroxymethylcytosine levels in the SPRY4 locus, promoting tumor development ( 70 ). Colorectal cancer (CRC) is a common malignant tumor in the digestive tract, and its metastasis is mainly related to uncontrolled proliferation. In 2021, Jia Guo et al. discovered that the expression level of SPRY4 in NCM460 cell lines, among four human CRC cell lines (SW620, SW480, LOVO, and HCT116), was the highest, while SW480 cell line had the lowest expression level. As a tumor suppressor gene, SPRY4 inhibits the proliferation, migration, and invasion of SW480 cells by regulating the MDM2/p53 pathway mediated by EZH2, and promotes apoptosis. SPRY4 overexpression inhibits tumor formation in vivo by reducing tumor size and weight ( 8 ). In 2023, Alexei J. Stuckel et al. analyzed the sequencing data of SPRY4 in gastric cancer tissues from the GEO database and TCGA database and found that the transcript levels of SPRY4 were increased in colorectal cancer patients compared to adjacent colonic and healthy mucosal control groups. This may be related to hypomethylation in the distal promoter region of CRC patients ( 68 ). DNA methylation is closely related to cancer development ( 71 ), and DNA methylation changes include hypermethylation and hypomethylation. Generally, high DNA methylation in the promoter region of a gene indicates gene silencing, while low DNA methylation indicates gene activation ( 72 ). Interestingly, Zhou et al. reported high methylation in the promoter region of SPRY4 in a limited number of CRC patients and found that the expression of SPRY4 was decreased in colorectal cancer tissues, significantly correlated with tumor invasion and advanced TNM stage. Furthermore, low expression of SPRY4 predicted poor prognosis in colorectal cancer ( 28 ). These research findings suggest that SPRY4, as a tumor suppressor in colorectal cancer, may have a complex role and be regulated by multiple factors, including gene expression regulation and epigenetic modifications. (Refer to the Table 3 for details). The role of SPRY4 in Diseases. MOG, Myelin oligodendrocyte glycoprotein; MEFs, Primary mouse embryonic fibroblasts; HEK-293T, human embryonic kidney (HEK) 293T cell; LLC cell, Lewis lung carcinoma; BMDMs, B16F10 melanoma cell; bone marrow-derived macrophages; PBMCs, Peripheral blood mononuclear cells; AMs, alveolar macrophages; BALF, Bronchoalveolar lavage fluid; (Spry4-MKO) mice, myeloid-specific Spry4 knockout; (Spry4-MTG) mice, macrophage-specific Spry4 transgenic; HUVEC, human vascular endothelial cells; WB, Western blotting; ICH, Immunohistochemistry; ISH, In situhybridization; IF, Immunofluorescence. NA, Not answered. Glioblastoma (GBM) is the most common brain tumor with poor prognosis. In 2008, cancer genomics researchers suggested that the amplification and mutation of RTK genes are one of the main causes of glioblastoma ( 86 ), and the dysregulation of RTK-induced pathways is a key step in driving the carcinogenic potential of brain cancer. Zhao et al. found that SPRY4 mRNA is significantly lower in GBM compared to adjacent brain tissues, and that SPRY4 inhibits the malignant behavior of GBM tumors. Additionally, SPRY4 is an independent prognostic factor in GBM, with high expression of SPRY4 being associated with better prognosis. SPRY4 inhibits GBM invasion by inhibiting ERK phosphorylation and ETS-1-induced matrix metalloproteinase 9 (MMP9) expression ( 80 ). Matrix metalloproteinases (MMPs) can disrupt the tissue barrier of tumor invasion by promoting extracellular matrix degradation, facilitating tumor infiltration through the basement membrane and extracellular matrix. By exogenous expression of SPRY4, the proliferation and migration of GBM-derived cell lines can be suppressed, further confirming the potential role of SPRY4 in inhibiting GBM ( 79 ). Therefore, SPRY4 may serve as a potential therapeutic target, and its upregulation or restoration of function may provide therapeutic benefits for GBM patients. However, further research is needed to validate these findings and explore the clinical application of SPRY4-related therapeutic strategies. Based on the anatomical location of the tumor, cholangiocarcinoma (CCA) can be divided into intrahepatic cholangiocarcinoma (ICC), perihilar cholangiocarcinoma (PHCC), distal cholangiocarcinoma (DCC), and other subtypes. PHCC is the most common subtype of CCA and has the poorest prognosis ( 87 ). Bo Qiu et al. confirmed that the expression of SPRY4 in PHCC tumor tissues was significantly lower than that in adjacent normal tissues, and overexpression of SPRY4 inhibited the malignant behavior of perihilar cholangiocarcinoma cells. The molecular mechanism by which SPRY4 exerts anti-cancer effects in perihilar cholangiocarcinoma is mainly related to ERK phosphorylation, which inhibits cell proliferation and migration. Additionally, SPRY4 is significantly associated with tumor size, lymphatic infiltration, and serves as an independent prognostic biomarker for PHCC ( 12 ). In conclusion, SPRY4 may act as a tumor suppressor in hilar cholangiocarcinoma by regulating ERK phosphorylation and affecting cell proliferation and migration, thereby impacting the malignancy of the tumor. Currently, there are fewer studies on SPRY4 in hepatocellular carcinoma (HCC). Sirivatanauksorn et al. found that the expression of SPRY4 was decreased compared to normal liver tissues but did not investigate its role in HCC development ( 73 ). Qingxia Ma et al. found that in sorafenib-resistant HCC patients, the histone deacetylase HDAC4 in complex with the transcription factor MEF2D to form a complex that directly binds to the SPRY4 promoter region to inhibit the transcriptional level of SPRY4, leading to overactivation of the MAPK/ERK pathway. They further found that the HDAC4 inhibitor tasquinimod induced SPRY4 expression and inhibited ERK activity, eliminating the resistance of HCC cells to sorafenib treatment ( 65 ). These findings provide new insights into the treatment of HCC, especially in dealing with drug resistance. In 2020, Chinese researchers analyzed the expression levels of SPRY4 in gastric cancer (GC) tissues from the TCGA database and found that SPRY4 was upregulated in human gastric cancer tissues, indicating that its expression levels were higher than in normal gastric tissues. Furthermore, the mRNA level of SPRY4 was validated in 78 cases of human gastric cancer tissues and non-gastric cancer tissues using RT-qPCR, confirming the high expression of SPRY4. High expression of SPRY4 is associated with several clinical pathological features of gastric cancer, including depth of infiltration, TNM staging, lymph node metastasis, and regional lymph node metastasis. High expression of SPRY4 is correlated with shorter median overall survival and median progression time, suggesting that it may serve as an adverse prognostic biomarker. In in vitro experiments, knockdown of SPRY4 expression in gastric cancer cell lines inhibited cell proliferation and migration. In in vivo experiments using a xenograft mouse model, the inhibition of tumor growth was observed upon knockdown of SPRY4 ( 81 ). Overall, this study reveals the potential of SPRY4 as an adverse prognostic biomarker and suggests its potential as a therapeutic target and prognostic biomarker. These findings provide important scientific evidence for future gastric cancer treatment strategies. Compared to normal human mammary epithelial cells (nHMEC), SPRY4 protein and mRNA expression were reduced in other breast cancer cell lines (BT20, MCF7, SKBR3, MDA-MB468, ZR-75), except for the MDA-MB231 cell line ( 36 , 88 , 89 ). Vanita Vanas et al. found that SPRY4 expression inhibits proliferation and migration of breast cancer cells by interfering with ERK phosphorylation and MAPK pathway activation ( 88 ). In contrast, inhibiting SPRY4 increased the protein level of β3-integrin, which promotes cell migration and invasion in vitro and lung metastasis in vivo in breast cancer cells ( 36 , 90 , 91 ). Hongyu Jing et al. first discovered that SPRY4 can regulate the characteristics of tumor stem cells. Knockdown of SPRY4 in MDA-MB-231 cells enhances tumor stem cell characteristics, including increased expression of CD133, CD44 subsets, and mammosphere formation. It also reduces sensitivity to paclitaxel treatment in vitro and enhances tumor formation in xenograft models, and this effect is not limited to MDA-MB-231 cells ( 36 ). In 2021, Ethan J. Brock et al. found that SPRY4 levels were significantly reduced in invasive ductal carcinoma compared to normal and ductal carcinoma in situ tissues. SPRY4 was highly expressed in ductal carcinoma in situ and decreased with the transition to invasive ductal carcinoma. They first revealed the role of SPRY4 in limiting the transition from pre-invasive lesions to invasive diseases, which was shown to be driven by a decrease in ERK/MAPK signaling transduction ( 56 ). MicroRNA-181 also has carcinogenic effects in breast cancer, partly due to targeting the 3’ untranslated region of SPRY4 ( 63 ). These findings suggest that SPRY4 may play a complex role in the occurrence, development, and treatment resistance of breast cancer. In some breast cancer cells, decreased expression of SPRY4 appears to be associated with the invasiveness and progression of cancer, while in other cases, the function of SPRY4 may be related to the inhibition of tumor growth and metastasis. Therefore, SPRY4 may have different biological significance and potential therapeutic target value in different subtypes and stages of breast cancer. In 2005, Winn et al. found that SPRY4 is highly expressed in non-small cell lung cancer cell lines that co-express Wnt-7a and Fzd-9 ( 92 ). When intracellular Wnt-7a binds to Fzd-9, it activates the MAPK signaling pathway. In this context, the upregulation of SPRY4 expression may serve as a feedback inhibitory response to this activation. Studies have also found that Wnt7A/Fzd9 signaling can increase Spry4 promoter activity through PPARγ, which further promotes the expression of SPRY4 ( 29 ). In 2006, they further discovered that the expression of Spry4 mRNA and protein was decreased in non‐small cell lung cancer (NSCLC) cell lines and poorly developed lung cell lines compared to untransformed human lung epithelial cell lines. In human NSCLC cell lines, SPRY4 inhibits cell proliferation, invasion and epithelial-mesenchymal transition. The MEK inhibitor trametinib inhibits the expression of SPRY4 in stromal-like KRAS mutant NSCLC, leading to the activation of AKT and ERK signals in stromal-like KRAS mutant lung cancer cells ( 29 ). This phenomenon explains why some patients with KRAS-mutant NSCLC may not respond well to MEK inhibitor therapy and highlights the need for combination treatment strategies to simultaneously inhibit MEK and other potential alternative proliferation signaling pathways, such as using inhibitors targeting the AKT signaling pathway. Additionally, osimertinib, a third-generation TKI targeting EGFR mutations, has been shown to decrease the expression of SPRY4 in PC-9 cells carrying EGFR mutations. This leads to the phosphorylation of AXL and sustained activation of the MAPK signaling pathway, which may be one of the reasons for the development of resistance ( 93 ). Recent studies have shown promising anticancer effects of SPRY4 in NSCLC. These effects are closely associated with the involvement of miR-411-5p/3p, which plays a key role in mediating the anti-tumor properties of Spry4 in this specific type of lung cancer. Research has demonstrated that the oncogenic microRNA-141 directly targets tumor suppressor genes such as SPRY4 and TXNIP, leading to their downregulation and promoting the progression of lung cancer ( 60 ). These research findings emphasize the complex role of SPRY4 in the development of NSCLC and how it interacts with tumor biology through different signaling pathways and molecular modulators. These discoveries provide potential targets for the development of new therapeutic strategies, including regulating the expression of microRNAs and combination therapy with inhibitors targeting specific signaling pathways. Common chromosomal abnormalities in acute myeloid leukemia (AML) include complete loss or partial loss of chromosome 5 and/or 7 ( 94 ). These chromosomal losses may contribute to the occurrence and progression of leukemia. As mentioned earlier, human SPRY4 is located on the long arm of chromosome 5. So, what is the role of SPRY4 in AML? Gain-of-function mutations in the KRAS and NRAS genes lead to sustained activation of the RAS pathway, resulting in dysregulated proliferation and differentiation of bone marrow cells, which is associated with poor prognosis in AML ( 77 ). SPRY4, as a negative regulator of the RAS pathway, plays a role in inhibiting cancer development. Knockdown of SPRY4 accelerates the occurrence and progression of AML, mainly by increasing RAS signaling to promote cancer development ( 77 ). Furthermore, the expression levels of SPRY4 differ significantly among AML patients with different risk groups, with higher levels associated with the low-risk group ( 75 ). This suggests that the expression levels of SPRY4 may contribute to the prognostic assessment of high-risk patients. Further studies have confirmed the loss of SPRY4 in secondary AML, present in both early stages and during progression or relapse ( 78 ). Therefore, SPRY4 may play a tumor-suppressive role in AML. Further research is needed to explore how the loss of SPRY4 affects patient prognosis and how it may serve as a therapeutic target. SPRY4 has been validated as a tumor suppressor gene in leukemia transgenic mouse models, and its disruption leads to the development of a lethal subtype in AML. Testicular germ cell tumors (TGCTs) have a relatively low incidence rate in China, approximately 46,000 per 100,000, and are one of the most common malignancies in males aged 20-35. Through a genome-wide association study, Kanetsky et al. discovered that TGCTs have a genetic susceptibility. KITLG and SPRY4 are potential susceptibility genes ( 95 ). Variations in SPRY4 (rs4624820) are associated with a decreased risk of GCT ( 96 ). Further research has shown that SPRY4 gene variants may also play an important role in the susceptibility to pediatric and adolescent GCTs ( 97 ). In addition, a specific SNP (rs10463352) in SPRY4 demonstrates significant parent-of-origin effects, with a significantly higher risk when transmitted from the mother to the offspring than from the father ( 98 ). Das et al. further investigated SPRY4 and found that it is highly expressed (both at the mRNA and protein levels) in human TGCT samples, whereas it is expressed at a lower level in normal adult testes. In TGCT cell lines (833 K and NT2-D1), reducing SPRY4 expression through siRNA leads to decreased activation of the PI3K/Akt signaling pathway, resulting in reduced cell growth, migration, and invasion, thereby promoting tumor development ( 51 ). On the other hand, members of the miR-302 family act as oncogenes by inducing SPRY4 expression and activating the MAPK/ERK and PI3K/Akt signaling pathways ( 50 ). Overall, these findings contribute to a deeper understanding of the genetics of TGCTs and may provide information for the development of screening strategies and treatment methods for this disease. In China, epithelial ovarian cancer (EOC) ranks third in the incidence rate among female reproductive system tumors, with an increasing trend, but it has the highest mortality rate among female reproductive malignancies. Hua KT discovered that the histone methyltransferase G9a inhibits the expression of the tumor suppressor gene SPRY4, thereby promoting the proliferation and metastasis of ovarian cancer cells ( 99 ). This may be related to SPRY4’s inhibition of the Ras/MAPK pathway. Targeting histone methyltransferase could potentially become a new approach for therapeutic intervention. So WK found that the mRNA levels of SPRY4 showed no significant changes in samples from EOC patients of different subtypes, but the mRNA levels of SPRY4 were lower in human EOC cell lines ( 76 ). Similarly, other researchers found a significant decrease in SPRY4 protein in EOC patient tissues ( 74 ). Deletion of the SPRY4 gene is rare in high-grade serous carcinoma samples ( 76 ). This suggests that SPRY4 may not play a role in the progression of high-grade serous ovarian cancer. Similarly, although SPRY4 protein expression is decreased in EOC patient tissues, analysis revealed no significant correlation between SPRY4 expression and tumor stage, recurrence, post-treatment ascites, and survival time. So what is the function and regulatory mechanism of SPRY4 in human ovarian cancer? So WK found that knocking down SPRY4 inhibited AREG-induced cancer cell invasion and migration. However, the role of SPRY4 in prostate cancer and lung cancer is completely different ( 100 ). In different tumor microenvironments, the role of SPRY4 may vary, and such context-dependent functions increase the complexity of cancer treatment. Gastrointestinal stromal tumors (GISTs) are rare tumors, with an annual incidence rate of approximately 10 to 15 cases per million people worldwide ( 101 ). The K641E mutation in the receptor tyrosine kinase gene KIT has been found in both sporadic and familial cases of GIST in humans ( 102 ). Currently, targeted therapy with KIT inhibitors is the main treatment for GIST. Researchers have found that Spry4 may be a potential therapeutic target for GISTs with oncogenic KIT mutations in Kit(K641E) mouse models ( 103 ). Although the authors discovered the impact of GIST-associated KIT mutations on cell gene expression, they did not study it in depth. In 2003, researchers found that downregulation of SPRY4A is a reliable predictor of response to imatinib therapy in GIST ( 82 ). Further studies have found that the protein level of SPRY4 in extracellular vesicles can be used to evaluate the response to imatinib therapy and disease status before and after treatment ( 104 ). In 2015, Thys A found that knocking down SPRY4 promotes proliferation of icc cells in the gastric antrum and colon of mice, but no activation of the ERK pathway was detected ( 105 ). Further research confirmed that SPRY4 has an inhibitory effect in GIST, as it can bind to KIT and inhibit its expression and activity, thereby reducing cell survival and proliferation. Additionally, SPRY4 acts as a sensitizing factor for imatinib, enhancing the efficacy of the drug. However, the role of SPRY4 is invalidated due to secondary resistant KIT mutations that occur during the treatment of GIST ( 83 ). In conclusion, it is speculated that targeting SPRY4 and KIT in combination with inhibitors such as imatinib may be more effective in GIST treatment. The increased level of SPRY4 protein in extracellular vesicles may be related to the selection of GIST to avoid negative feedback interference in the KIT pathway.

SPRY4, also known as sprouty RTK signaling antagonist 4(Sprouty4), is a gene that encodes a protein belonging to the Spry family. This family consists of proteins that are rich in cysteine and proline ( 1 , 2 ). The SPRY4 protein is an inhibitor of the receptor transduction MAPK signaling pathway. It is an intracellular protein that translocates to the plasma membrane upon activation, with its structural domain located in the cytoplasmic membrane ( 3 ). With a molecular weight of approximately 32.541 KDa, SPRY4 is involved in various cellular biological functions under both physiological and pathological conditions. In addition to its role in embryonic development and organogenesis ( 4 , 5 ), SPRY4 is also associated with cell apoptosis and proliferation, oxidative stress, inflammatory response, and ischemic injury ( 1 , 6 – 11 ). Furthermore, SPRY4 plays a significant role in the occurrence and development of tumors ( 12 ). This review article summarizes recent research on SPRY4, focusing on its research progress in various diseases.

Barbara Haigl and colleagues have found that both hypoxic conditions and treatment with deferoxamine (DFO) can increase the expression of SPRY4 ( 106 ). The increased expression of SPRY4 may be achieved through enhanced gene transcription and mRNA stability. Koji Taniguchi and colleagues have discovered the mechanism of action of Spry4 under hypoxic conditions. Compared to wild-type (WT) mice, Spry4 knockout (KO) mice show greater resistance to hindlimb ischemia and soft tissue ischemia, as the absence of Spry4 accelerates neovascularization, resulting in significantly higher rates of hindlimb blood flow recovery in the KO mice after induction of hindlimb ischemia ( 11 ). These results suggest that SPRY4 may be a novel target for treating peripheral ischemic diseases. Additionally, studies have found that downregulation of the Spry2/4 genes has neuroprotective effects. This may be due to the promotion of astrocyte proliferation in the ischemic brain injury area by reducing Spry2/4 expression, resulting in reduced neuronal cell death and the size of the injury area ( 83 ). These findings further support the protective role of SPRY4 in limb ischemic injury and cerebral ischemic neural injury, providing potential directions for the development of new treatment methods or drug targets. However, further research is needed to validate these findings and evaluate the clinical feasibility of potential therapeutic strategies. (Refer to the Table 2 for details).

SPRY4 protein assumes a pivotal role in the regulation of the RTK pathway, governing crucial aspects of organogenesis, developmental processes, and the emergence of malignant neoplasms. The significance of SPRY proteins varies across distinct cellular lineages, contingent upon the contextual milieu. In certain tumor types, the SPRY4 gene exerts its influence as a tumor suppressor, effectively quelling the malignant propensities of cancerous cells. Nevertheless, within the realm of gastric cancer, it metamorphoses into an oncogene, fueling the pernicious advancement of the ailment. Moreover, SPRY4 manifests its potential as a prognostic biomarker in specific cancers. The presence of oncogenic RAS mutations within certain tumors governs the dysregulation and functional manifestation of SPRY4. Furthermore, SPRY4 orchestrates the development of inflammatory maladies. At present, researchers ardently examine the expression and functionality of SPRY4 within tumor microenvironments, striving to fathom its intricate involvement in the malignant conduct of cancer cells. The relentless pursuit of utilizing SPRY4 as a promising target for anti-cancer therapeutics, aimed at enhancing tumor prognoses and surmounting drug resistance, remains an active field of investigation. However, the quest for small molecule activators that emulate the functionality of SPRY4 remains elusive.

HP: Conceptualization, Writing – original draft, Writing – review & editing. RX: Software, Visualization, Writing – review & editing. YZ: Funding acquisition, Investigation, Supervision, Writing – original draft, Writing – review & editing.