HCV Core Protein–ISX Axis Promotes Chronic Liver Disease Progression via Metabolic Remodeling and Immune Suppression

Chronic hepatitis C virus (HCV) infection is an important public health issue. However, knowledge on how the virus remodels the metabolic and immune response toward hepatic pathologic environment is limited. The transcriptomic and multiple evidences reveal that the HCV core protein–intestine‐specific homeobox (ISX) axis promotes a spectrum of metabolic, fibrogenic, and immune modulators (e.g., kynurenine, PD‐L1, and B7‐2), regulating HCV‐infection relevant pathogenic phenotype in vitro and in vivo. In a transgenic mice model, the HCV core protein–ISX axis enhance metabolic disturbance (particularly lipid and glucose metabolism) and immune suppression, and finally, chronic liver fibrosis in a high‐fat diet (HFD)‐induced disease model. Mechanistically, cells with HCV JFH‐1 replicons upregulate ISX and, consequently, the expressions of metabolic, fibrosis progenitor, and immune modulators via core protein‐induced nuclear factor‐κB signaling. Conversely, cells with specific ISX shRNAi inhibit HCV core protein‐induced metabolic disturbance and immune suppression. Clinically, the HCV core level is significantly correlated with ISX, IDOs, PD‐L1, and B7‐2 levels in HCC patients with HCV infection. Therefore, it highlights the significance of HCV core protein–ISX axis as an important mechanism in the development of HCV‐induced chronic liver disease and can be a specific therapeutic target clinically.