Cell-specific roles of autophagy in liver fibrosis: implications for targeted pharmacotherapy

Liver fibrosis represents a pivotal stage in the progression from chronic liver disease to cirrhosis, characterized by intricate pathological alterations in both parenchymal and non-parenchymal cells. Autophagy, a fundamental mechanism for maintaining intracellular homeostasis, plays a critical role in these processes. This study aims to elucidate the cell type-specific roles of autophagy in liver fibrosis and propose targeted intervention strategies.

We systematically reviewed the functional roles of autophagy in hepatocytes, macrophages, hepatic stellate cells (HSCs), and liver sinusoidal endothelial cells (LSECs) by analyzing current experimental and mechanistic evidence. We further conceptualized therapeutic approaches based on selective modulation of autophagic activity in different cell populations.

In hepatocytes, autophagy exerts protective effects by reducing lipid accumulation and preventing apoptosis caused by lipid metabolism disorders. In macrophages, autophagy regulates polarization and suppresses inflammatory cytokine release, thereby attenuating inflammation and slowing fibrosis progression. Conversely, autophagy in HSCs and LSECs exhibits dual effects: it may accelerate fibrosis by promoting cell activation and extracellular matrix remodeling or mitigate fibrosis by inhibiting these processes. These findings underscore the cell context-dependent role of autophagy during fibrogenesis.

Selective enhancement or inhibition of autophagy in distinct liver cell types offers a promising strategy for regulating fibrosis. This approach provides new insights and a theoretical basis for developing targeted therapies for liver fibrosis.