Targeting p97/Valosin-Containing Protein Promotes Hepatic Stellate Cell Senescence and Mitigates Liver Fibrosis

Liver fibrosis, one of the main histological determinants of various chronic liver diseases, currently lacks effective treatment. Hepatic stellate cells (HSCs) are pivotal in the production of extracellular matrix and amplify the fibrogenic response. Inhibiting the activation of HSCs or promoting the senescence of activated HSCs is crucial for the regression of liver fibrosis. The ATPase p97, also known as valosin-containing protein (VCP), is a central component of the ubiquitin-proteasome system, and it regulates numerous cellular processes by influencing protein homeostasis. In this study, we observed an upregulation of p97 expression around regions exhibiting fibrosis in a diet- and chemical-induced nonalcoholic steatohepatitis and fibrosis murine model. Intervention with the p97 antagonist CB-5083 or the knockdown of p97 reduced the expression of alpha-smooth muscle actin and collagen-I in both mouse or human HSCs. The administration of CB-5083 induced HSC senescence and resulted in the upregulation of senescence markers, including p21, p53, GPX4, and senescence-associated β-galactosidase. Furthermore, CB-5083 treatment also inhibited the expression of Yes-associated protein (YAP), which is also a senescence-related regulatory protein and has a profibrotic function. We used CB-5083 to treat fibrotic mice and found that the activation of HSCs was inhibited, and the liver fibrosis was attenuated. In addition, in vivo experiments confirmed that CB-5083 facilitated HSC senescence and reduced YAP expression. These findings underscore the potential of pharmacological targeting p97/VCP to induce HSC senescence and alleviate liver fibrosis.