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

Urolithin A alleviated cellular senescence markers in D-galactose-induced aging models.

• UA suppressed expression of senescence markers p53 and p21 in D-galactose-induced macrophage senescence models.
• The study used D-galactose (D-gal) to induce macrophage senescence in vitro and liver aging in vivo.
• Effects were assessed using Western blotting as a primary methodology.

Urolithin A modulated inflammatory cytokine expression in aging-associated inflammation.

• UA suppressed pro-inflammatory factors IL-6 and IL-1β.
• UA elevated the anti-inflammatory cytokine IL-10.
• These effects were observed in the context of D-galactose-induced macrophage senescence and mouse liver aging models.

Urolithin A enhanced Nur77 protein stability by inhibiting MDM2-mediated ubiquitination and degradation.

• The mechanism was investigated using molecular docking, Western blotting, and immunoprecipitation.
• UA inhibited MDM2-mediated ubiquitination of Nur77, thereby preventing its proteasomal degradation.
• Stabilization of Nur77 protein was identified as the mechanistic basis for restoration of inflammatory homeostasis.
• The MDM2-Nur77 axis is identified as a potential therapeutic target for hepatic aging.

Urolithin A ameliorated D-galactose-induced liver injury in vivo.

• In vivo experiments used a D-galactose-induced mouse liver aging model.
• UA treatment ameliorated D-gal-induced liver injury.
• UA modulated the hepatic Nur77-MDM2 axis in vivo, consistent with in vitro mechanistic findings.

Nur77 is subject to MDM2-mediated ubiquitination and degradation in the context of hepatic aging.

• MDM2 was identified as the E3 ubiquitin ligase responsible for Nur77 ubiquitination.
• Ubiquitination and subsequent degradation of Nur77 was implicated in the disruption of inflammatory homeostasis during aging.
• Immunoprecipitation was used to confirm the interaction between MDM2 and Nur77.
• Molecular docking was used to investigate the UA-Nur77 interaction.