Abstract
Chronic alcohol consumption can lead to alcohol live disease (ALD). Steatosis is a critical hallmark of ALD, making it an important stage 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. We employ 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 unveils that SSa primarily acts through the mTOR and PPAR-α signaling pathways in the liver. Biophysical assays and loss of function experiments confirm SGA directly binds to and modulates the activity of SIRT1 protein, mitigating ethanol-induced cell injury via the SIRT1-mTOR-PPAR-α axis. Furthermore, SGA displays a survival prolonging advantage compared to resveratrol for treating ALD. This suggests SGA holds promise as a potential therapeutic agent for ALD.