p16 ^Ink4a ‐Positive Hepatocytes Drive Liver Fibrosis Through Activation of LIFR Family Pathway

ABSTRACT As organs undergo the process of aging, they exhibit signs of progressive fibrosis, a hallmark of aging that is observed in various organs, including the liver, kidneys, and lungs. Liver fibrosis is a particularly deleterious outcome of the healing processes that occur during the repair of chronic liver injury. It is widely accepted that the majority of these injuries are initially triggered by hepatocytes. Indeed, elderly patients have been shown to be more prone to developing liver fibrosis following hepatic injury. However, the mechanisms by which aging promotes fibrotic processes remain to be elucidated. The preceding observation, indicating a robust correlation between the severity of fibrosis in human cirrhotic patients and the population of hepatocytes expressing elevated levels of p16 ^Ink4a (p16 ^h ), proposes that p16 ^h hepatocytes might serve as initiators of fibrogenic processes in response to liver injury. In this study, we employed a CCl ₄ ‐induced hepatitis model to promote a fibrogenic process and observed the accumulation of p16 ^h hepatocytes in zone 3. These p16 ^h cells manifest numerous senescent characteristics, and their accumulation has been strongly correlated with the severity of liver fibrosis. Selective elimination of p16 ^h hepatocytes has been shown to ameliorate CCl ₄ ‐induced liver fibrosis, presumably through the suppression of hepatic stellate cell activation. Single‐cell transcriptomic analysis revealed that murine and human hepatocytes up‐regulated Ctf1 or Lif, the ligands of the LIFR signaling pathway. The administration of LIFR ligands has been demonstrated to enhance the phosphorylation of STAT3, and the LIFR inhibitor rescued the fibrogenic phenotype in hepatic stellate cells induced by secreted factors from senescent hepatocytes. This finding offers potential therapeutic insights for the management of liver fibrosis.