Chemoproteomics reveals baicalin activates hepatic CPT1 to ameliorate diet-induced obesity and hepatic steatosis

Significance Baicalin is a major flavonoid component from the herbal medicine Scutellaria baicalensis that has been shown to have an antisteatosis effect. Through quantitative chemoproteomic profiling, we discovered that baicalin acts as a natural allosteric activator of carnitine palmitoyltransferase 1 (CPT1), the rate-limiting enzyme of fatty acid β-oxidation (FAO). By directly binding to CPT1 and activating its activity to accelerate fatty acid degradation, baicalin can significantly ameliorate symptoms associated with hepatic steatosis and reduce diet-induced obesity (DIO). Our study provides an example of a natural product agonist for CPT1. The results provide mechanistic insights to explain the bioactivity of baicalin in reducing lipid accumulation and introduce exciting opportunities for developing novel flavonoid-based FAO activators for pharmacologically treating DIO and associated metabolic disorders.