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

Summary

Hyperuricemia causally impairs erectile function via a defined molecular pathway: uric acid binds MLCK (N803), blocks NEDD4L-mediated ubiquitination, stabilizes MLCK, and increases MLC2 phosphorylation to promote cavernosal contraction. Urate-lowering therapies or MLCK inhibition reverse dysfunction in rats, and human data link elevated uric acid to >2.5-fold ED risk in younger adults.

Key Findings

• Elevated serum uric acid is associated with >2.5-fold increased ED risk in adults aged 24–49 years.
• Urate oxidase knockout rats develop early erectile dysfunction absent other metabolic comorbidities.
• Uric acid binds MLCK at N803, inhibits NEDD4L-mediated ubiquitination, stabilizes MLCK, increases MLC2 phosphorylation, and promotes cavernosal smooth muscle contraction.
• Urate-lowering agents (febuxostat, benzbromarone, 3170) or MLCK inhibitor (ML-7) restore erectile function in rats.

Clinical Implications

Supports screening and treatment of hyperuricemia in men with erectile dysfunction and motivates trials of urate-lowering or MLCK-modulating therapies to improve erectile outcomes, especially in younger patients without comorbidities.

Limitations

• Human data are associative; no randomized interventional studies demonstrating ED improvement with urate lowering
• Translational applicability from rat models to diverse human ED etiologies requires validation

Future Directions

Conduct randomized controlled trials testing urate-lowering strategies on erectile function, develop selective MLCK/NEDD4L pathway modulators for cavernosal smooth muscle, and define biomarkers predicting response.