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Despite the involvement of many genes in spermatogenesis, the precise processes remain unclear. The critical E3 ubiquitin ligase <jats:italic>Rnf126<\/jats:italic> regulates essential cellular processes through ubiquitination-induced protein degradation. It plays a significant role in DNA repair, immune response, and signaling cascades, underscoring its central importance in maintaining cellular homeostasis. However, the mechanisms by which <jats:italic>Rnf126<\/jats:italic> controls spermatogenesis are not fully understood. This research identifies <jats:italic>Rnf126<\/jats:italic> as a crucial component in sperm flagellar biogenesis and germ cell development. Through genetic lineage tracing, we show that RNF126 is highly expressed in sperm cells and weakly expressed in Sertoli cells. The germ epithelium of RNF126 deficiencies is characterized by a loss of germ cells due to an increase in germ cell apoptosis at various stages of development, which ultimately results in vesiculation of the spermatogenic tubule. Targeting <jats:italic>Rnf126<\/jats:italic> results in different types of germ cells reduction, infertility, and microtubule-associated motor activity failure (MMAF), characterized by spermatozoa with truncated, twisted, and malformed flagella. Detailed ultrastructural studies reveal the extent of flagellar damage in the absence of <jats:italic>Rnf126<\/jats:italic>, highlighting its critical role in maintaining flagellar stability. An important finding is the interaction between RNF126 and BAG6, which regulates sperm synthesis and germ cell development. Clinically, reduced RNF126 levels in sperm from individuals with oligoasthenoteratospermia are significantly different from those in fertile individuals. Investigating <jats:italic>Rnf126<\/jats:italic> function in spermatogenesis, together with empirical findings on MMAF presentation, may improve our understanding of the developmental processes involved in sperm flagellum formation and contribute to elucidating the causes of male infertility.<\/jats:p>","DOI":"10.1038\/s41420-025-02432-w","type":"journal-article","created":{"date-parts":[[2025,5,23]],"date-time":"2025-05-23T19:16:33Z","timestamp":1748027793000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Absence of Rnf126 causes male infertility with multiple morphological abnormalities of the sperm flagella"],"prefix":"10.1038","volume":"11","author":[{"given":"Shengnan","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zihan","family":"Qin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiaohua","family":"Xiong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zexiao","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-3877-7489","authenticated-orcid":false,"given":"Yuming","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,23]]},"reference":[{"key":"2432_CR1","unstructured":"GBD 2021 Tobacco Forecasting Collaborators. 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Participants who were included in the study provided informed consent. The animals\u2019 experiment had approval from The Fifth Affiliated Hospital of Sun Yat-sen University Animal Experimentation Ethics Committee (No. 00234).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}],"article-number":"251"}}