Tyrosine kinase inhibitor neratinib attenuates liver fibrosis by targeting activated hepatic stellate cells

Abstract

Liver fbrosis, a common outcome of chronic liver disease characterized by excessive accumulation of extracellular matrix (ECM), is a leading cause of mortality worldwide. The tyrosine kinase inhibitor neratinib is a human epidermal growth factor receptor 2 (HER2) inhibitor approved by the FDA for HER2-positive breast cancer treatment

however, it has not yet been evaluated for liver fbrosis treatment. We elucidated the anti-fbrotic efects of neratinib in hepatic stellate cells (HSCs) and in vivo models of CCl4-induced liver fbrosis. HSC activation is a key step in liver fbrogenesis and has a crucial role in collagen deposition, as it is primarily responsible for excessive ECM production. The efect of neratinib on HSC was evaluated in transforming growth factor (TGF-β)-incubated LX-2 cells and culture-activated primary human HSCs. In vivo study results indicated that neratinib inhibited the infammatory response, HSC diferentiation, and collagen accumulation induced by CCl4. Moreover, the anti-fbrotic efects of neratinib were not associated with the HER2 signaling pathways. Neratinib inhibited FGF2 expression in activated HSCs and serum FGF2 level in the model, suggesting that neratinib possessed therapeutic potency against liver fbrosis and the potential for application against other fbrotic diseases.