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Recent studies have highlighted a close relationship between palmitic acid (PA) and endothelial cell ferroptosis. Here, we demonstrate that PA promotes the ubiquitination\u2010dependent degradation of SRPK1 mediated by the E3 ubiquitin ligase mindbomb 1 (MIB1) at lysine 494. Moreover, SRPK1 S\u2010palmitoylation is catalyzed by zinc\u2010finger DHHC S\u2010acyltransferase 24 (ZDHHC24) at cysteines 188\/502\/647\u00a0and deacylated by acyl protein thioesterase 1 (APT1). The dynamic S\u2010palmitoylation of SRPK1 can strengthen SRPK1\u2010MIB1 interaction, facilitate its ubiquitination, and thereby affect protein stability. Furthermore, SRPK1 modulates the phosphorylation of p53 tumor suppressor protein (p53) at serine 15, which may promote its nuclear translocation and activation under PA stimulation or in high\u2010fat\u2010diet\u2010fed animal models. The crucial effect of SRPK1 on p53 activation contributes to the suppression of endothelial cell ferroptosis in the context of lipid accumulation. Additionally, in silico screening reveals that 4'\u2010O\u2010Methylochnaflavone interacts with SRPK1, which effectively stabilizes SRPK1 and alleviates PA\u2010induced ferroptosis. Collectively, these findings underscore the critical role of PA in regulating endothelial cell ferroptosis via SRPK1 S\u2010palmitoylation and p53 activation, providing potential therapeutic strategies for dyslipidemia\u2010related erectile dysfunction.<\/jats:p>","DOI":"10.1002\/advs.202513796","type":"journal-article","created":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T20:06:08Z","timestamp":1769717168000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Palmitoylation\u2010Mediated Ubiquitination of SRPK1 Regulates Ferroptosis in High\u2010Fat\u2010Induced Erectile Dysfunction"],"prefix":"10.1002","volume":"13","author":[{"given":"Xiao\u2010Hui","family":"Tan","sequence":"first","affiliation":[{"name":"Department of Urology Peking University First Hospital  Beijing P. R. China"},{"name":"Institute of Urology Peking University  Beijing P. R. China"},{"name":"National Urological Cancer Center  Beijing P. 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