Pharmacological Inhibition of STAT3 Pathway Ameliorates Acute Liver Injury in Vivo Via Inactivation of Inflammatory Macrophages and Hepatic Stellate Cells

Liver diseases represent a major health problem worldwide, in particular, acute liver injury is associated with high mortality and morbidity. Inflammatory macrophages and hepatic stellate cells (HSCs) are known to be involved in the pathogenesis of acute liver injury. In this study, we have investigated the implication of STAT3 inhibition in acute liver injury/early fibrogenesis. In fibrotic human livers, we found STAT3 mRNA expression was significantly upregulated and correlated with collagen I expression. In vitro, STAT3 signaling pathway was found to be activated in TGF beta-activated HSCs and inflammatory macrophages. STAT3 inhibitor, WP1066 significantly inhibited TGF beta-induced collagen I, vimentin and alpha-SMA expression, and contractility in human HSCs. In LPS- and IFN gamma-induced pro-inflammatory macrophages, WP1066 strongly attenuated nitric-oxide release and expression of major inflammatory markers such as TNF-alpha, iNOS, CCL2, IL-1 beta, IL-6, and CCR2. In vivo in CCl4-induced acute liver injury mouse model, WP1066 significantly reduced collagen expression, HSCs activation, and intrahepatic inflammation. Finally, in LPS-induced human hepatic 3D spheroid model, WP1066 inhibited LPS-induced fibrotic and inflammatory parameters. In conclusion, our results demonstrate that the therapeutic inhibition of STAT3 pathway using WP1066 targeting HSCs and inflammatory macrophages suggests a potential pharmacological approach for the treatment of acute liver injury.