Saikogenin A improves ethanol-induced liver injury by targeting SIRT1 to modulate lipid metabolism

Chronic alcohol consumption leads to a spectrum of liver disorders, including steatosis, inflammation, and fibrosis, collectively known as alcohol liver disease (ALD). Steatosis is a critical hallmark of ALD, making it an important target for therapeutic intervention. Saikosaponin A (SSa), a compound found in Radix Bupleuri, has previously shown promising hepatoprotective, anti-inflammatory, and antioxidant properties. However, its role in ALD remains understudied, with direct regulatory targets and mechanisms yet to be fully elucidated in vivo. Moreover, the instability of SSa in gastric juice raises questions about the efficacy of oral SSa solutions. In this study, we employed cell-based screening models and a chronic-plus-binge ethanol-fed mouse model to investigate the protective mechanisms of SSa and its metabolite Saikogenin A (SGA), against ethanol-induced hepatocyte injury. Our RNA-seq analysis in mice unveiled that SSa primarily acts through the mTOR and PPAR-α signaling pathways in the liver. Biophysical assays and loss-of-function experiments confirmed that SGA directly binds to and modulates the activity of the SIRT1 protein, mitigating ethanol-induced cell injury via the SIRT1-mTOR-PPAR-α axis. Furthermore, our liver-specific knockdown of SIRT1 in an ALD mouse model demonstrated that the action of the liver proteins affected by oral SSa solutions is mediated through SIRT1. Significantly, SGA displayed a superior safety profile for hepatocytes compared to SSa. Our findings highlight the role of SGA in binding to the SIRT1 protein and enhancing its activity, thereby regulating hepatic fatty acid oxidation and adipogenesis in ALD. This suggests that SGA holds promise as a potential therapeutic agent for ALD.