Elevated uric acid induces erectile dysfunction in rats by interacting with MLCK and inhibiting its ubiquitin-mediated degradation

Erectile dysfunction, a precursor to cardiovascular diseases, is linked to metabolic disorders like gout. However, whether hyperuricemia plays a direct causative role in erectile dysfunction is unclear. Here we show that clinical data from young patients (24–49 years) reveal an over 2.5-fold increased erectile dysfunction risk with elevated serum uric acid. In spontaneous hyperuricemia rats with Urate oxidase gene knockout, hyperuricemia impairs erectile function early (20 weeks) without other metabolic comorbidities. Mechanistically, uric acid enters corpus cavernosum smooth muscle cells, interacting with MLCK at N803 to inhibit its ubiquitination by E3 ligase NEDD4L, stabilizing MLCK and increasing MLC2 phosphorylation, and leading to corpus cavernosum contraction. Pharmacological uric acid-lowering (febuxostat, benzbromarone, 3170) or MLCK inhibition (ML-7) restores erectile function in rats. Our findings reveal the key molecules and mechanisms of hyperuricemia-induced erectile dysfunction, which provides evidence for hyperuricemia or gout patients to control uric acid levels and prevent erectile dysfunction. Elevated uric acid induces early erectile dysfunction by interacting with MLCK and by inhibiting its ubiquitin-mediated degradation. MLCK inhibitor ML-7 and uric acid-lowering therapy improve erectile function induced by hyperuricemia.