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SMEK1 is recognized as a regulatory subunit of the protein phosphatase 4 complex. However, its potential phosphatase\u2010independent functions in mammalian meiosis remain largely unexplored. Given the association of genetic variants near the SMEK1 locus with human infertility, we sought to define its specific role and mechanism in murine spermatogenesis. We generated a germ cell\u2010specific\n                    <jats:italic>Smek1<\/jats:italic>\n                    knockout mice model by crossing\n                    <jats:italic>Smek1<\/jats:italic>\n                    <jats:sup>f\/f<\/jats:sup>\n                    mice with\n                    <jats:italic>Stra8<\/jats:italic>\n                    <jats:sup>GFP<\/jats:sup>\n                    \u2010Cre mice. The phenotypic consequences were mainly assessed by histological analysis, chromosome spreading, and immunofluorescence staining. The molecular mechanisms were predominantly investigated using chromatin\u2010immunoprecipitation, luciferase reporter assays, and co\u2010immunoprecipitation analysis both in\u00a0vivo and in\u00a0vitro studies. Germ cell\u2010specific ablation of\n                    <jats:italic>Smek1<\/jats:italic>\n                    resulted in complete sterility due to a total arrest of spermatogenesis. The deficiency of\n                    <jats:italic>Smek1<\/jats:italic>\n                    caused severe defects in prophase I, including an increased proportion of diplotene\u2010stage spermatocytes, impaired synaptonemal complex dynamics, incomplete DSB repair, and a reduction in crossover. Notably, a subset of spermatocytes survived the initial checkpoint monitoring but arrested at metaphase I with a disrupted spindle structure and hyperactivation of the spindle assembly checkpoint. Mechanistically, we identified that SMEK1 functions independently of PP4 as a transcriptional repressor. It binds to the promoter of the deubiquitinating enzyme gene\n                    <jats:italic>USP10<\/jats:italic>\n                    . In the absence of SMEK1, increased USP10 protein stabilized BUBR1 (the core spindle assembly checkpoint component) and therefore delayed further progression beyond the metaphase I stage. Our study discovered a novel role for SMEK1 as a transcriptional regulator essential for meiotic progression. This SMEK1\u2010USP10\u2010BUBR1 pathway provides a fundamental mechanistic insight into the causes of male infertility and identifies a potential therapeutic target for human azoospermia and infertility.\n                  <\/jats:p>","DOI":"10.1096\/fj.202600580rr","type":"journal-article","created":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T05:04:20Z","timestamp":1777266260000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<i>Smek1<\/i>\n                    \u2010Dependent Transcriptional Repression of\n                    <i>Usp10<\/i>\n                    Is Essential for the Progression of Murine Spermatogenesis"],"prefix":"10.1096","volume":"40","author":[{"given":"Ai","family":"Liu","sequence":"first","affiliation":[{"name":"Key Laboratory of Experimental Teratology, Ministry of Education and Department of Medical Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine Shandong 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