Physcion alleviates alcoholic hepatic inflammation and pyroptosis through SIRT1-AMPK signaling axis

Objective Physcion is an active component of Rheum rhaponticum which is a low-sugar, high-fiber food. It has also demonstrated antimicrobial, anti-inflammatory, and hepatoprotective properties. This study investigated the protective effect of physcion on alcohol-associated liver disease (ALD) and the associated molecular mechanisms. Methods In vivo , the National Institute of Alcohol Abuse and Alcoholism (NIAAA) chronic alcohol-fed model was established in male C57BL/6 mice, placing them on Lieber-DeCarli ethanol-containing diets for ten days and then administering a single dose of ethanol (5 g/kg) via gavage. In vitro , human hepatic stellate cells LX-2 were treated with ethanol and physcion, sirtuin 1 (SIRT1) agonists, adenosine monophosphate-activated protein kinase (AMPK) agonists for 24 h. Target gene and protein expression were determined by real-time PCR and Western blotting. Results Physcion effectively ameliorated ALD-induced serum aminotransferase and triglyceride levels, steatosis, activated SIRT1-AMPK signaling, and blocked hepatic NOD-like receptor protein 3 (NLRP3) inflammasome activation and gasdermin D (GSDMD) relevant in pyroptosis, similar to hepato-protection of AMPK and SIRT1 agonists. Furthermore, physcion blocked the accumulation of high-mobility group box 1 (HMGB1) and nuclear translocation and release of nuclear factor- κ B (NF- κ B) p65. Importantly, silencing SIRT1-AMPK signaling abolished the protective effect of physcion. Conclusion These findings strongly demonstrated that SIRT1-AMPK signaling activation plays a role in ALD pathogenesis, and physcion alleviates this effect by inhibiting NLRP3 inflammasome activation, inflammatory response, and pyroptosis. In this view, manipulating hepatic inflammation and pyroptosis via strategies targeting SIRT1-AMPK signaling holds a high therapeutic potential for ALD.