Discovery of a Novel Silybin Derivative for the Treatment of Metabolic Dysfunction-Associated Steatohepatitis

MASH has become the leading cause of liver disease worldwide, and the prevalence of MASH is steadily increasing. The development of new drugs for the treatment of MASH is urgent. Silybin has been used for decades in liver protection, but its insufficient antioxidant capacity and poor oral bioavailability have limited its clinical use. In this paper, we discovered a novel silybin derivative A2 as a potent agent for MASH treatment. In vitro, A2 showed excellent activity in inhibiting lipid accumulation, antioxidation, anti-inflammation, and antifibrosis. In the acute-liver-damage rat model experiment, A2 showed notable hepatoprotective efficacy. In the MASH mouse model experiment, A2, better than silybin, significantly ameliorated the pathological features of the MASH liver including steatosis, inflammation, and fibrosis. In addition, A2 displayed a good oral bioavailability and a good safety profile. Collectively, these findings demonstrated that A2 serves as a promising candidate for MASH treatment.