Abstract

The high prevalence of diabetes mellitus-induced erectile dysfunction (DMED) in males and the limited efficacy of existing therapies necessitate deeper mechanistic insights. We identify pathological lactate accumulation in the corpus cavernosum as a major driver of DMED in male mice, promoting structural degeneration and smooth muscle cell loss. Mechanistically, transcriptional repression and functional impairment of fructose-1,6-bisphosphatase 1 ( Fbp1 ), a rate-limiting gluconeogenic enzyme, underlie this lactate accumulation. Epigenetic profiling revealed suppression of Fbp1 transcription associated with histone H3 lysine 9 trimethylation and histone H3 lysine 27 trimethylation. Palmitoylation at the FBP1 Cys282 residue, catalyzed by zinc finger DHHC-type containing 13, further disrupted its gluconeogenic function, exacerbating lactate accumulation. To rescue these defects, we engineered lipid nanoparticles loaded with the Fbp1 -C282S mutant mRNA, restoring FBP1 expression, blocking pathological palmitoylation, and ultimately improving erectile function in diabetic male mice. Here, our study in male mice identifies cavernosal lactate accumulation as a central pathological factor, elucidates its molecular regulation, and provide a targeted therapeutic strategy for DMED. The study identifies cavernosal lactate as a driver of diabetes-induced erectile dysfunction through FBP1 dysfunction, histone methylation and palmitoylation.