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

Jiaqi Xiao, Lihua Qu, Xuan Qin, Chao Chen, Yuan Xu, Xinyu Que, Yaoyao Ma, Wentao Huang, Haoxiang Ou, Chao Wu, Yongfen Bao, Shigang Shan

Hubei Key Laboratory of Diabetes and Angiopathy, School of Pharmacy, Hubei University of Science and Technology, Xianning 437000, China. · pubmed

Paper

Abstract

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.

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Research summary

Urolithin A stabilizes Nur77 by inhibiting its ubiquitination, alleviating hepatic aging-associated inflammation. This study addresses a mechanism related to aging and inflammation, which are central to the aging process and age-related diseases.

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