Enhanced Expression of ARK5 in Hepatic Stellate Cell and Hepatocyte Synergistically Promote Liver Fibrosis

AMPK-related protein kinase 5 (ARK5) is involved in a broad spectrum of physiological and cell events, and aberrant expression of ARK5 has been observed in a wide variety of solid tumors, including liver cancer. However, the role of ARK5 in liver fibrosis remains largely unexplored. We found that ARK5 expression was elevated in mouse fibrotic livers, and showed a positive correlation with the progression of liver fibrosis. ARK5 was highly expressed not only in activated hepatic stellate cells (HSCs), but also in hepatocytes. In HSCs, ARK5 prevents the degradation of transforming growth factor β type I receptor (TβRI) and mothers against decapentaplegic homolog 4 (Smad4) proteins by inhibiting the expression of Smad ubiquitin regulatory factor 2 (Smurf2), thus maintaining the continuous transduction of the transforming growth factor β (TGF-β) signaling pathway, which is essential for cell activation, proliferation and survival. In hepatocytes, ARK5 induces the occurrence of epithelial-mesenchymal transition (EMT), and also promotes the secretion of inflammatory factors. Inflammatory factors, in turn, further enhance the activation of HSCs and deepen the degree of liver fibrosis. Notably, we demonstrated in a mouse model that targeting ARK5 with the selective inhibitor HTH-01-015 attenuates CCl₄-induced liver fibrosis in mice. Taken together, the results indicate that ARK5 is a critical driver of liver fibrosis, and promotes liver fibrosis by synergy between HSCs and hepatocytes.