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TM4 cells and mice were treated with FSH, and assessments included cell viability, testicular histology, and key ferroptosis markers (ferrous iron, malondialdehyde malondialdehyde, glutathione glutathione). Molecular expression was analyzed via quantitative real-time PCR and western blot. The role of ferroptosis was further examined using the inhibitor ferrostatin-1 (Fer-1). RNA sequencing was employed to explore underlying mechanisms, and functional validation was performed through knockdown and overexpression of the identified regulator, fibroblast growth factor 21 (FGF21). Our results demonstrate that FSH exposure induces ferroptosis in both TM4 Sertoli cells and mouse testes. This is evidenced by decreased protein levels of the ferroptosis suppressors SLC7A11 and FSP1, increased levels of the stress-response proteins FTH1 and HO1, elevated ferrous ion and malondialdehyde content, and reduced glutathione. This ferroptotic cell death may represent a key mechanism contributing to FSH-associated testicular damage. Notably, the ferroptosis inhibitor ferrostatin-1 effectively mitigated this process in TM4 cells. Transcriptomic analysis not only confirmed FSH-induced ferroptosis but also identified FGF21 as a potential modulator. Knockdown of FGF21 promoted ferroptosis, whereas supplementation with exogenous FGF21 alleviated FSH-induced ferroptosis, suggesting a novel inhibitory role for FGF21 in this pathway. In summary, our findings establish that FSH can induce testicular ferroptosis and identify FGF21 as a potential endogenous mitigator of this effect. This highlights FGF21 as a promising therapeutic target for preventing or treating FSH-induced testicular damage.<\/jats:p>","DOI":"10.1093\/reprod\/xaag001","type":"journal-article","created":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T12:21:32Z","timestamp":1767615692000},"source":"Crossref","is-referenced-by-count":1,"title":["Fibroblast growth factor 21 attenuates FSH-induced ferroptosis in TM4 Sertoli cells"],"prefix":"10.1093","volume":"171","author":[{"given":"Shiming","family":"Wang","sequence":"first","affiliation":[{"name":"Reproductive Medical Center, The First Affiliated Hospital of Zhengzhou University , Zhengzhou,","place":["China"]},{"name":"Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University , Nanjing,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaping","family":"Liu","sequence":"additional","affiliation":[{"name":"Reproductive Medical Center, The First Affiliated Hospital of Zhengzhou University , Zhengzhou,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nannan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University , Zhengzhou,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deyu","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Vascular Surgery, The Fifth Affiliated Hospital of Zhengzhou University , Zhengzhou,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Liu","sequence":"additional","affiliation":[{"name":"Reproductive Medical Center, The First Affiliated Hospital of Zhengzhou University , Zhengzhou,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haixia","family":"Jin","sequence":"additional","affiliation":[{"name":"Reproductive Medical Center, The First Affiliated Hospital of Zhengzhou University , Zhengzhou,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7174-9989","authenticated-orcid":false,"given":"Guidong","family":"Yao","sequence":"additional","affiliation":[{"name":"Reproductive Medical Center, The First Affiliated Hospital of Zhengzhou University , Zhengzhou,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingchun","family":"Su","sequence":"additional","affiliation":[{"name":"Reproductive Medical Center, The First Affiliated Hospital of Zhengzhou University , 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