{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T11:18:06Z","timestamp":1783423086156,"version":"3.54.6"},"reference-count":21,"publisher":"IMR Press","issue":"6","license":[{"start":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T00:00:00Z","timestamp":1782172800000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["31701074"],"award-info":[{"award-number":["31701074"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Front. Biosci. (Landmark Ed)"],"abstract":"<jats:p>Background:Male infertility, often caused by oligospermia, is a major global health concern. Hypoxia is a known inducer of germ cell death, a process governed by the hypoxia-inducible factor 1\u03b1 (HIF-1\u03b1). The methyltransferase Set7 represses HIF-1\u03b1 activity, but its specific role in the hypoxic male germline remains unknown.Method:The mouse spermatogonia-derived GC-2 cell line was used. The effect of hypoxia on SET domain-containing lysine methyltransferase 7 (Setd7) mRNA expression was assessed by quantitative real-time polymerase chain reaction (qRT-PCR). Cells were transfected with a Set7 overexpression plasmid, and its impact was measured via luciferase reporter assays using an erythropoietin (EPO) promoter and qRT-PCR for HIF-1\u03b1 targets (glucose transporter 1 (Glut1), phosphoglycerate kinase 1 (Pgk1), pyruvate kinase, muscle (Pkm)). Stable cell lines expressing wild-type Set7 or a catalytically dead mutant (Set7-H297A) were generated. Apoptosis under hypoxia was analyzed by flow cytometry and fluorescence microscopy.Results:Hypoxia (1% O2) significantly suppressed Setd7 mRNA expression while inducing HIF-1\u03b1 target gene expression (Glut1, Pgk1, vascular endothelial growth factor (Vegf), Pkm). Set7 overexpression inhibited hypoxia-induced EPO promoter activity and blunted the hypoxic induction of Glut1, Pgk1, and Pkm. Although Set7 overexpression did not alter HIF-1\u03b1 protein levels, it markedly increased hypoxia-induced apoptosis. This pro-apoptotic effect was significantly attenuated in cells expressing the enzymatically inactive Set7-H297A mutant.Conclusion:Set7 represses the essential HIF-1\u03b1-mediated adaptive response to hypoxia in spermatogonial cells. Paradoxically, this repression potentiates hypoxia-induced apoptosis in a methyltransferase-dependent manner. These findings identify Set7 as a critical molecular switch that shifts cells from cellular adaptation to death under hypoxic stress, suggesting a regulatory pathway potentially relevant to hypoxia-associated male infertility.<\/jats:p>","DOI":"10.31083\/fbl50226","type":"journal-article","created":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T10:50:51Z","timestamp":1783421451000},"source":"Crossref","is-referenced-by-count":0,"title":["Set7-Mediated Repression of the HIF-1\u03b1 Adaptive Response Triggers Apoptosis in Hypoxic Spermatogonia"],"prefix":"10.31083","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-5392-8123","authenticated-orcid":true,"given":"Yangyang","family":"Song","sequence":"first","affiliation":[{"name":"Medical Genetics Center, Maternal and Child Health Hospital of Hubei Province, 430070 Wuhan, Hubei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4629-4799","authenticated-orcid":true,"given":"Zhu","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Reproduction, Maternal and Child Health Hospital of Hubei Province, 430070 Wuhan, Hubei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5926-9037","authenticated-orcid":true,"given":"Jieping","family":"Song","sequence":"additional","affiliation":[{"name":"Medical Genetics Center, Maternal and Child Health Hospital of Hubei Province, 430070 Wuhan, Hubei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-5256-6793","authenticated-orcid":true,"given":"Jie","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Reproduction, Maternal and Child Health Hospital of Hubei Province, 430070 Wuhan, Hubei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2026,6,23]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Sun H, Gong TT, Jiang YT, Zhang S, Zhao YH, Wu QJ. 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