ZDHHC9‐Mediated Palmitoylation of ACSL4 Drives Ferroptosis in Diabetes Mellitus–Induced Erectile Dysfunction

Diabetes mellitus-induced erectile dysfunction (DMED) is a highly prevalent complication among diabetic patients; however, its underlying pathogenic mechanisms remain incompletely understood. Metabolic disorder is a hallmark of diabetes, yet its precise contribution to DMED progression is not well defined. In this study, we demonstrate that metabolic disturbances, particularly elevated levels of palmitic acid (PA), induce ferroptosis in corpus cavernosum fibroblasts, thereby contributing to the development of erectile dysfunction. Mechanistically, we identified ZDHHC9, a palmitoyltransferase, to be aberrantly upregulated in DMED, where it catalyzes the S-palmitoylation of ACSL4 at cysteine 595. This post-translational modification enhances ACSL4 enzymatic activity, promotes lipid peroxidation, and drives ferroptosis in fibroblasts. Furthermore, we found that hyperactivation of the PI3K/AKT signaling pathway serves as a key upstream regulator of ZDHHC9 expression in this context. To explore the therapeutic potential of targeting this pathway, we developed siRNA against Zdhhc9 encapsulated in lipid nanoparticles (siZdhhc9-LNPs), which effectively suppressed Zdhhc9 expression in the corpus cavernosum and ameliorated erectile dysfunction in DMED mice. Collectively, our findings reveal a pathological cascade linking metabolic dysregulation to fibroblast ferroptosis via ZDHHC9-mediated ACSL4 palmitoylation, and establish ZDHHC9 as a promising therapeutic target for the treatment of DMED.