Urolithin A Attenuates Aging-Induced Liver Injury by Inhibiting Nur77 Ubiquitination and Degradation

Aging is accompanied by chronic low-grade inflammation (inflammaging), driving age-related diseases. Urolithin A (UA), a gut microbial metabolite, possesses anti-inflammatory properties, yet its mechanism in hepatic aging remains unclear. This study investigated UA’s effects on aging-associated inflammation and the involvement of Nur77 in D-galactose-induced macrophage senescence and mouse liver aging models using molecular docking, Western blotting, and immunoprecipitation. UA alleviated cellular senescence markers (p53, p21), suppressed pro-inflammatory factors (IL-6, IL-1β), and elevated anti-inflammatory IL-10. Mechanistically, UA enhanced Nur77 protein stability by inhibiting MDM2-mediated ubiquitination and degradation, thereby restoring inflammatory homeostasis. In vivo, UA ameliorated D-gal-induced liver injury and modulated the hepatic Nur77-MDM2 axis. Conclusion: UA stabilizes Nur77 by inhibiting its ubiquitination, alleviating hepatic aging-associated inflammation. This study identifies the MDM2-Nur77 axis as a potential therapeutic target for hepatic aging.