Src kinase as a potential therapeutic target in non‐alcoholic and alcoholic steatohepatitis

Abstract Non‐alcoholic steatohepatitis (NASH) and alcohol‐associated (ASH) are the major cause of liver‐related mortality with limited therapeutic options available. In this study, we investigated role Src tyrosine kinase in pathogenesis (N)ASH. We examined expression livers from patients NASH, ASH, cirrhosis biliary atresia, preclinical mouse models: methionine choline deficient (MCD)‐diet‐induced Lieber–DeCarli ethanol (EtOH)‐diet‐induced carbon tetrachloride (CCl 4 )‐ bile duct ligation (BDL)‐induced liver fibrosis. Functional studies, using inhibitor KX2‐391, were performed NASH ASH models, relevant vitro models. Transcriptomic analysis revealed increased human diseased that positively correlated disease progression. inhibition ameliorated lipid biosynthesis (steatosis); monocytes/macrophages infiltration inflammatory cytokines (inflammation) hepatic stellate cells (HSCs) activation collagen (fibrosis) MCD‐diet EtOH‐diet induced attenuated FFA‐induced hepatocytic accumulation, LPS/IFNγ‐induced nitric oxide release several signatures macrophages TGFβ‐induced HSCs activation, contractility expression. Moreover, diminished gene markers LPS/IFNγ‐stimulated BMDMs LPS‐stimulated PCLS, reduced FA macrophage deposition 3D spheroids. Mechanistic studies further mediated effects through FAK/PI3K/AKT pathway. Our results demonstrate a multicellular functional highlighting as promising target (non)alcoholic steatohepatitis.