SU5, a Stable Auraptene Analog, Ameliorates Metabolic Dysfunction-Associated Steatohepatitis Through Modulation of the FXR Signaling Pathway.

Abstract

Metabolic Dysfunction-Associated Steatohepatitis (MASH), a metabolic liver disease severely threatening public health, is characterized by hepatic steatosis, inflammatory infiltration, and fibrotic progression. Currently, there is still a lack of specific therapeutic approaches for MASH in clinical practice. Auraptene (AUR), a natural citrus-derived compound with demonstrated therapeutic potential against MASH, is limited in clinical translation by poor metabolic stability. To address this challenge, we evaluated the effects and mechanisms of SU5, a novel auraptene analog engineered for enhanced metabolic stability, in a MASH mouse model induced by a high-fat/high-sugar diet combined with carbon tetrachloride (CCl4). SU5 treatment effectively reduced hepatic steatosis, inflammation, and fibrosis in MASH mice. It activated the FXR pathway, regulating bile acid metabolism-related genes. SU5 also suppressed lipogenic genes, decreased inflammatory factors, and restored lipid homeostasis. Outperforming auraptene, SU5 is a promising MASH treatment option due to its enhanced stability.