Abstract
Although therapies based on direct-acting antivirals (DAAs) effectively eradicate hepatitis C virus (HCV) in patients, there is still a high risk of liver fibrosis even after a sustained virological response. Therefore, it is of great clinical importance to understand the mechanism of potential factors that promote liver fibrosis after virological cure by treatment with DAAs. Here, we found that tubulointerstitial nephritis antigen-like 1 (TINAGL1) is significantly increased in HCV-infected hepatocytes and in the liver of patients with liver fibrosis, and that higher TINAGL1 expression persists in HCV-eradicated hepatocytes after treatment with DAAs. Overexpression of TINAGL1 in the liver triggers and exacerbates liver fibrosis, and xenotransplantation of HCV-eradicated Huh7.5 cells leads to a higher risk of hepatocellular carcinoma. Conversely, knockdown of TINAGL1 expression prevents and attenuates the progression of liver fibrosis in mice. TINAGL1 binds and stabilizes platelet-derived growth factor-BB (PDGF-BB) in hepatocytes, leading to an increase in intracellular and extracellular PDGF-BB, which sensitizes the PDGF-BB/PDGFRβ pathway to activate hepatic stellate cells. This study highlights that TINAGL1 is a new factor contributing to liver fibrosis after injury, including but not limited to HCV infection, even after virological cure by DAAs, and emphasizes the therapeutic potential of TINAGL1 as an innovative target for the treatment of liver fibrosis.