{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T15:17:31Z","timestamp":1767712651990,"version":"3.48.0"},"reference-count":60,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T00:00:00Z","timestamp":1767657600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32270516"],"award-info":[{"award-number":["32270516"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Testosterone (T) produced by Leydig cells (LCs) is essential for male reproduction; yet, the regulatory mechanisms underlying steroidogenesis remain incompletely understood. Here, we investigated the role of cyclin-dependent kinase 5 regulatory subunit-associated protein 3 (CDK5RAP3) in Leydig cell development and steroidogenesis, based on its identification by immunoprecipitation-mass spectrometry (IP-MS) as a protein associated with steroidogenesis and cholesterol metabolism in mouse testicular tissue. Using human samples, we found that CDK5RAP3 expression was significantly reduced in Leydig cells from patients with spermatogenic failure (T &lt; 10.4 nmol\/L). Notably, CDK5RAP3 expression increased during mouse postnatal Leydig cell maturation and regeneration in an ethane dimethanesulfonate (EDS)-induced rat model. Functional analyses in primary LCs and MLTC-1 cells showed that hCG stimulation triggered CDK5RAP3 nuclear translocation without altering its overall expression, while CDK5RAP3 knockdown markedly impaired hCG-induced testosterone production and reduced the expression of the steroidogenic regulator steroidogenic acute regulatory (STAR) protein, as well as key steroidgenic enzymes, including cytochrome P450 family 11 subfamily A member 1 (CYP11A1), 17a-hydroxylase (CYP17A1), and 3\u03b2-hydroxysteroid dehydrogenase (HSD3B). Conversely, CDK5RAP3 overexpression enhanced testosterone production in the absence of hCG. In vivo, AAV2\/9-mediated CDK5RAP3 silencing in adult mouse testes resulted in a significant reduction in serum testosterone levels compared with controls (3.60 \u00b1 0.38 ng\/mL vs. 1.83 \u00b1 0.37 ng\/mL). Mechanistically, CDK5RAP3 interacted with SMAD4 and CEBPB, and BMP pathway inhibition by Noggin rescued the testosterone deficit caused by CDK5RAP3 loss. Together, these findings identify CDK5RAP3 as an essential regulator of Leydig cell steroidogenesis and provide insight into its potential relevance to male infertility associated with low testosterone.<\/jats:p>","DOI":"10.3390\/ijms27020586","type":"journal-article","created":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T15:09:36Z","timestamp":1767712176000},"page":"586","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["CDK5RAP3 Regulates Testosterone Production in Mouse Leydig Cells"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-7108-8000","authenticated-orcid":false,"given":"Jian","family":"Ruan","sequence":"first","affiliation":[{"name":"College of Life Sciences, Anhui Normal University, Wuhu 241000, China"},{"name":"College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qianyi","family":"Dong","sequence":"additional","affiliation":[{"name":"College of Life Sciences, Anhui Normal University, Wuhu 241000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yufan","family":"Jin","sequence":"additional","affiliation":[{"name":"College of Life Sciences, Anhui Normal University, Wuhu 241000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuhong","family":"Yang","sequence":"additional","affiliation":[{"name":"College of Life Sciences, Anhui Normal University, Wuhu 241000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"Li","sequence":"additional","affiliation":[{"name":"College of Life Sciences, Anhui Normal University, Wuhu 241000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yafei","family":"Cai","sequence":"additional","affiliation":[{"name":"College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1007\/s11154-022-09712-1","article-title":"Testosterone treatment of late-onset hypogonadism\u2014Benefits and risks","volume":"23","author":"Snyder","year":"2022","journal-title":"Rev. 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