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 (CCl 4 ). 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.