Chemoproteomics identifies STAT3 as a key target of baicalin in ameliorating liver fibrosis

Abstract Liver fibrosis results from an imbalance between the deposition and degradation of the extracellular matrix in the liver, where there are currently no effective therapeutic drugs available. In this study, we demonstrated that baicalin, a major active component of the traditional Chinese medicine Scutellaria baicalensis, was able to inhibit the activation of hepatic stellate cells and attenuate liver fibrosis in various mouse models. In order to elucidate the molecular basis of its anti-fibrotic effects, we designed a novel baicalin photo-crosslinking probe and applied a quantitative chemoproteomic strategy based on dimethyl labeling to profile baicalin-interacting proteins. Aided by systematic gene knockouts of these potential baicalin interactors, we identified STAT3 as a key target in mediating the anti-fibrotic function of baicalin. Mechanistically, baicalin primarily binds to the N-terminal domain of STAT3, inhibits its interaction with JAK2 and thereby suppresses STAT3 phosphorylation. Our findings reveal the molecular mechanism of baicalin’s anti-fibrotic effects and provide a theoretical basis for the design of new anti-fibrotic drugs based on the structure of baicalin.