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As one of the most important endocrine disruptors, DBP has male reproductive toxicity and can lead to testicular dysfunction. In view of the fact that Leydig cells are important functional and structural units in the testis, their damage will affect testicular function. However, the underlying mechanism of DBP\u2010caused damage to mouse Leydig cells remains elusive. In the study, it is confirmed that DBP can promote the expression of death\u2010associated protein kinase 3 (DAPK3), thereby inducing autophagy of mouse Leydig cells by using in vivo and in vitro experiments. Also, bioinformatics analysis and molecular biology experimental techniques are utilized to further demonstrate that DBP\u2010induced upregulation of DAPK3 results from both the activated transcription by specific protein 2 (Sp2) and the decreased ubiquitination and degradation by parkin RBR E3 ubiquitin\u2010protein ligase (PRKN). Interestingly, melatonin can inhibit both Sp2\/DAPK3 and PRKN\/DAPK3 signaling pathways by inhibiting oxidative stress, thereby alleviating DBP\u2010induced autophagy of mouse Leydig cells. Overall, the study unravels a novel regulatory mechanism of DBP\u2010induced autophagy of mouse Leydig cells and identifies DAPK3 as a potential therapeutic target for DBP\u2010caused damage to the male reproductive system.<\/jats:p>","DOI":"10.1002\/advs.202413936","type":"journal-article","created":{"date-parts":[[2025,3,11]],"date-time":"2025-03-11T17:18:09Z","timestamp":1741713489000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["DAPK3 is Essential for DBP\u2010Induced Autophagy of Mouse Leydig Cells"],"prefix":"10.1002","volume":"12","author":[{"given":"Si","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Physiology School of Basic Medical Sciences Jiangxi Medical College Nanchang University  Nanchang 330006 P. R. 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