{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T22:20:03Z","timestamp":1783635603033,"version":"3.55.0"},"reference-count":47,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T00:00:00Z","timestamp":1756944000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Luzhou Municipal People\u2019s Government and Southwest Medical University","award":["2023LZXNYDJ001"],"award-info":[{"award-number":["2023LZXNYDJ001"]}]},{"name":"Luzhou Municipal People\u2019s Government and Southwest Medical University","award":["2023MVDKL-G1"],"award-info":[{"award-number":["2023MVDKL-G1"]}]},{"name":"Open Project Program of Metabolic Vascular Diseases Key Laboratory of Sichuan Province","award":["2023LZXNYDJ001"],"award-info":[{"award-number":["2023LZXNYDJ001"]}]},{"name":"Open Project Program of Metabolic Vascular Diseases Key Laboratory of Sichuan Province","award":["2023MVDKL-G1"],"award-info":[{"award-number":["2023MVDKL-G1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The maturation of testicular Leydig cells during the prepubertal stage is crucial for establishing male fertility. While diabetes is recognized as a significant detrimental factor affecting male testicular function, its impact specifically during the prepubertal period remains largely unknown. We hypothesized that prepubertal diabetes may impair testicular development by disrupting Leydig cell maturation. Using streptozotocin (STZ) administration, we established a prepubertal diabetic rat model and investigated the effects of diabetes on testicular development 2 and 4 weeks post-STZ treatment. Diabetes significantly hampered testicular development, manifesting as a decreased testicular weight, structural abnormalities, reduced testosterone levels, and increased inflammatory responses. As anticipated, prepubertal diabetes stagnated Leydig cell maturation and increased Leydig cell apoptosis. Mechanistic studies revealed that autophagy is essential for maintaining homeostasis and facilitating differentiation in immature Leydig cells but is significantly inhibited by hyperglycemia. Dysregulation of autophagy impaired the mitochondrial network, triggering inflammatory responses, suppressing steroidogenic capacity, and accumulating reactive oxygen species (ROS). Elevated ROS levels exacerbated the inflammatory response in the Leydig cells in an NLRP3-dependent manner. Inhibition of NLRP3 ameliorated the hyperglycemia-induced inflammation and decline in steroidogenic ability. Collectively, these findings demonstrate that hyperglycemia suppresses autophagy induction and enhances ROS accumulation in Leydig cells. This cascade promotes inflammation and inhibits steroidogenesis, thereby impeding testicular development in prepubertal diabetic rats.<\/jats:p>","DOI":"10.3390\/cells14171376","type":"journal-article","created":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T10:55:37Z","timestamp":1756983337000},"page":"1376","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Prepubertal Diabetes Stagnates Testicular Development by Skewing Autophagy Homeostasis in Leydig Cells"],"prefix":"10.3390","volume":"14","author":[{"given":"Zonghao","family":"Tang","sequence":"first","affiliation":[{"name":"Basic Medicine Research Innovation Center for Cardiometabolic Diseases, Ministry of Education, Southwest Medical University, Luzhou 646000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4852-5247","authenticated-orcid":false,"given":"Youkun","family":"Zheng","sequence":"additional","affiliation":[{"name":"Basic Medicine Research Innovation Center for Cardiometabolic Diseases, Ministry of Education, Southwest Medical University, Luzhou 646000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1038\/s41573-022-00500-9","article-title":"The glymphatic system: Implications for drugs for central nervous system diseases","volume":"21","author":"Lohela","year":"2022","journal-title":"Nat. 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