The NLRP3 inflammasome in the pathogenesis of erectile dysfunction: mechanistic insights and therapeutic potential

The NLRP3 inflammasome is a critical innate immune sensor that drives inflammatory responses and has been implicated in various chronic diseases. However, its specific role in erectile dysfunction (ED) remains incompletely understood, and the evidence supporting its clinical relevance has not been systematically evaluated.

This narrative review followed a structured literature search in PubMed, Web of Science, and Scopus from inception to 2026, using predefined keyword combinations covering NLRP3 inflammasome, pyroptosis, oxidative stress, endothelial dysfunction, neuroinflammation, endocrine dysregulation, and targeted inhibitors. Inclusion criteria comprised original studies, systematic reviews, and meta-analyses reporting NLRP3-related mechanisms or interventions in ED, without restriction to animal or human studies. The retrieved evidence was critically appraised, and the level of evidence was graded according to the Oxford Centre for Evidence-Based Medicine (OCEBM 2011) classification.

Preclinical studies, predominantly in rodent models of diabetic, hypertensive, and hyperuricaemic ED, consistently show NLRP3 upregulation/activation in penile tissues and improvement of erectile function after NLRP3-targeting interventions. Mechanistically, NLRP3 contributes to ED through three interrelated pathways: (1) endothelial dysfunction via pyroptosis and reduced nitric oxide bioavailability; (2) neuroinflammation affecting both peripheral autonomic nerves and central regulatory circuits; and (3) endocrine dysregulation, particularly impairment of Leydig cell steroidogenesis and testosterone production. Pharmacological inhibitors (MCC950, CY-09), IL-1 receptor antagonists, caspase-1 inhibitors, and natural products (curcumin, resveratrol) have shown efficacy in animal models; however, human data are limited to biomarker analyses, and no clinical trials have been reported for ED.

Current evidence supports a functional association and causal plausibility of NLRP3 inflammasome in ED pathogenesis, but direct causality in humans remains unconfirmed. Future research should prioritize rigorous causal validation, on-target specificity verification, and clinically aligned endpoints to facilitate translation of NLRP3-targeted strategies into ED therapeutics.