Carabrone Attenuates Metabolic Dysfunction–Associated Steatohepatitis by Targeting STAT3 in Mice

Metabolic dysfunction-associated steatohepatitis (MASH) has become one of the most common progressive liver diseases worldwide, but effective treatment options are severely unmet. Carabrone, a sesquiterpene lactone from the traditional Chinese herb <i>Carpesium abrotanoides </i>L., shows various pharmacological properties, whereas its effect on the improvement of MASH and the underlying mechanisms have not yet been reported. In this work, we revealed for the first time the beneficial effect of carabrone on MASH, including reducing liver lipid accumulation, inflammatory cell infiltration, and fibrosis in multiple diet-induced mice. Carabrone also alleviated lipid accumulation and inflammation in palmitic acid/oleic acid-stimulated hepatocytes. Mechanically, we identified signal transducers and transcriptional activator 3 (STAT3) as a key target of carabrone for treating MASH through quantitative chemical proteomic analysis, as well as the verification by the overexpression of STAT3 in vivo and in vitro. Further studies demonstrated that carabrone blocks MASH progression by inhibiting the activation of STAT3. More importantly, a new carabrone derivative <b>CA-21</b> with stronger anti-MASH activity and affinity for STAT3 was discovered through rational structural modification. Taken together, our findings suggest that carabrone and <b>CA-21</b> could be developed as promising drug candidates for MASH treatment.