Palmitoylation‐Mediated Ubiquitination of SRPK1 Regulates Ferroptosis in High‐Fat‐Induced Erectile Dysfunction

Serine-arginine protein kinase 1 (SRPK1) is a major protein kinase involved in mRNA splicing, cell cycle, and endothelial function. Recent studies have highlighted a close relationship between palmitic acid (PA) and endothelial cell ferroptosis. Here, we demonstrate that PA promotes the ubiquitination-dependent degradation of SRPK1 mediated by the E3 ubiquitin ligase mindbomb 1 (MIB1) at lysine 494. Moreover, SRPK1 S-palmitoylation is catalyzed by zinc-finger DHHC S-acyltransferase 24 (ZDHHC24) at cysteines 188/502/647 and deacylated by acyl protein thioesterase 1 (APT1). The dynamic S-palmitoylation of SRPK1 can strengthen SRPK1-MIB1 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-fat-diet-fed 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'-O-Methylochnaflavone interacts with SRPK1, which effectively stabilizes SRPK1 and alleviates PA-induced ferroptosis. Collectively, these findings underscore the critical role of PA in regulating endothelial cell ferroptosis via SRPK1 S-palmitoylation and p53 activation, providing potential therapeutic strategies for dyslipidemia-related erectile dysfunction.