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In this study, we focused on epigenetic regulators upregulated during differentiation as potential targets. Through a small-molecule screen targeting such conserved regulators, we found that PRMT5 inhibition suppressed mouse SSC differentiation and enhanced their proliferation in a GDNF-deficient, differentiation-prone microenvironment in vitro. Using SSC transplantation assays, we confirmed that EPZ015666-treated SSCs retained their spermatogonial identity. This differentiation-inhibitory effect was reversible upon EPZ015666 withdrawal, allowing restoration of normal spermatogenesis. Notably, EPZ015666 also inhibited differentiation and promoted the proliferation of human and non-human primate spermatogonia in vitro. Mechanistically, EPZ015666 exerted this effect by inhibiting the enzymatic active site of PRMT5. These findings suggest that PRMT5 inhibition could provide a novel strategy for culturing human SSCs in vitro.<\/jats:p>","DOI":"10.1186\/s13619-026-00293-x","type":"journal-article","created":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T00:01:38Z","timestamp":1783382498000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["PRMT5 inhibition promotes cross-species spermatogonia expansion and suppresses differentiation"],"prefix":"10.1186","volume":"15","author":[{"given":"Zhaokai","family":"Yao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kang","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuning","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaofang","family":"Ren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yetian","family":"Weng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linzi","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dingyao","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoxu","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jialin","family":"Wan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaoting","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaohui","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Yang","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,7]]},"reference":[{"issue":"5","key":"293_CR1","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1038\/nrn812","volume":"3","author":"MS Airaksinen","year":"2002","unstructured":"Airaksinen MS, Saarma M. 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All experiments involving human samples were performed in accordance with the ethical principles of the World Medical Association (Declaration of Helsinki). The study protocol was approved by the Medical Ethics Committee of The Third Affiliated Hospital of Guangzhou Medical University (Approval No. [2024] 031). Tissues were obtained from two patients with obstructive azoospermia, and informed consent was secured from all participants prior to sample collection.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"X.Z., C.L., Z.Y., F.L. have filed a patent related to this work. The remaining authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"22"}}