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Therefore, clarifying the targets and molecular mechanisms of radiotherapy resistance in ESCC is of great theoretical and clinical significance to enhance the efficacy of radiotherapy. In this study, GPR37 was identified as a key factor facilitating ESCC radiosensitization. We found that GPR37 is lowly expressed in ESCC, especially in radioresistant ESCC tumors. And its insufficiency is related to the malignant characteristics and unfavorable prognosis in ESCC. Further investigation revealed that GPR37 level is inversely regulated by promoter methylation but positively regulated by ZNF750. Functionally, GPR37 could not only overcome radioresistance of ESCC, but also inhibit proliferation, migration, and invasion. Mechanistically, GPR37 interacts with the ATP1A1 protein, effectively promoting its ubiquitination-induced degradation, thereby limiting the activation of the AKT\/mTOR signaling pathway. Additionally, GPR37 can be transported to recipient cells via exosomes and inhibit the malignant behavior of recipient cells. Overall, these findings suggest that GPR37-ATP1A1 axis holds potential as a therapeutic target for the management of ESCC, especially for overcoming radiation resistance.<\/jats:p>","DOI":"10.1038\/s41419-024-07240-1","type":"journal-article","created":{"date-parts":[[2024,12,27]],"date-time":"2024-12-27T10:29:18Z","timestamp":1735295358000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["GPR37-enhanced ubiquitination of ATP1A1 inhibits tumor progression and radiation resistance in esophageal squamous cell carcinoma"],"prefix":"10.1038","volume":"15","author":[{"given":"Jiaru","family":"Hu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Meng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1889-7018","authenticated-orcid":false,"given":"Lei","family":"Lv","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fu","family":"Hong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tian","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiqiang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5143-8828","authenticated-orcid":false,"given":"Qiyi","family":"Yi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9005-6005","authenticated-orcid":false,"given":"Liting","family":"Qian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,12,27]]},"reference":[{"key":"7240_CR1","doi-asserted-by":"publisher","first-page":"e342","DOI":"10.1016\/S1470-2045(20)30073-5","volume":"21","author":"W Wei","year":"2020","unstructured":"Wei W, Zeng H, Zheng R, Zhang S, An L, Chen R, et al. 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And the conclusion of the funded project requires that the author's affiliation must be detailed to the department.","order":7,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"Human specimens and protocols used in this study were approved by the Medical Research Ethics Committee of the First Affiliated Hospital of the University of Science and Technology of China (Approval No. 2021KY-140), and written informed consent was obtained from all patients. The animal study protocol was approved by the Institutional Animal Care and Use Committee of the University of Science and Technology of China (2022-N(A)-96), and the volume of the subcutaneous tumor does not exceed the required maximum tumor size of 1000\u2009mm\n                      3\n                      .","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}}],"article-number":"933"}}