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Spermatogonia are vulnerable to various external damaging factors, which can cause cell death. However, the mechanism is still unclear. In this study, we found that the actin-related protein T2 (ACTRT2) is specifically expressed in testicular tissue and is associated with spermatogenesis. In vitro, when GC-1 cells (spermatogonial cell line) were treated with busulfan, the proportion of cell death in the low-ACTRT2 group increased significantly. Reactive oxygen species accumulation and typical mitochondrial changes associated with ferroptosis occurred. In vivo, the seminiferous tubules in ACTRT2\u2212\/\u2212 mice were significantly shrunken. In addition, after being treated with busulfan, spermatogenesis in ACTRT2+\/\u2212 mice decreased significantly compared to that in wild-type mice. In ACTRT2+\/\u2212 testes, the expression levels of acyl-CoA synthetase long-chain family member 4 and arachidonic acid 15-lipoxygenase-1 (ALOX15) were upregulated, while the expression levels of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) were downregulated. Finally, we found that the expression of solute carrier family 11 member 2 (SLC11A2), iron responsive element binding protein 2 (IREB2), and transferrin receptor protein 1 (TFRC) increased significantly in the low-ACTRT2 group, which transports iron into the cell to increase the intracellular unstable iron pool. In conclusion, ACTRT2 deficiency leads to intracellular iron overload and damage to mitochondria, ultimately increasing spermatogonia vulnerability to ferroptosis.<\/jats:p>","DOI":"10.1093\/molehr\/gaaf041","type":"journal-article","created":{"date-parts":[[2025,8,12]],"date-time":"2025-08-12T11:39:19Z","timestamp":1754998759000},"source":"Crossref","is-referenced-by-count":6,"title":["ACTRT2 deficiency increases spermatogonia vulnerability to ferroptosis"],"prefix":"10.1093","volume":"31","author":[{"given":"Haicheng","family":"Chen","sequence":"first","affiliation":[{"name":"Reproductive Medicine Center, The Sixth Affiliated Hospital of Sun Yat-sen University , Guangzhou,","place":["People\u2019s Republic of China"]},{"name":"Biomedical Innovation Center, The Sixth Affiliated Hospital of Sun Yat-sen University , Guangzhou,","place":["People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanqing","family":"Li","sequence":"additional","affiliation":[{"name":"Reproductive Medicine Center, The Sixth Affiliated Hospital of Sun Yat-sen University , Guangzhou,","place":["People\u2019s Republic of China"]},{"name":"Biomedical Innovation Center, The Sixth Affiliated Hospital of Sun Yat-sen University , Guangzhou,","place":["People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daosheng","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Urology, Dongguan People\u2019s Hospital, The Tenth Affiliated Hospital of Southern Medical University , Dongguan,","place":["People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Andrology, The First Affiliated Hospital of Sun Yat-sen University , 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