Significance: Ample evidence has demonstrated an important role for autophagy as either a protective mechanism or a cause for hepatotoxicity, denoting the likely potentials for targeting autophagy in the prevention or treatment of hepatotoxicity. Recent Advances: The functional role of autophagy in the pathogenesis of hepatotoxicity has been gradually recognized. Mechanistically, the autophagy-mediated protective or promoting effect on hepatotoxicity is attributed to its functions in regulation of oxidative stress, endoplasmic reticulum (ER) stress, lipid metabolism, iron homeostasis, inflammatory response, and programmed cell death. Targeting autophagy as a novel strategy for fighting against hepatotoxicity has demonstrated encouraging efficacy in a number of models. Critical Issues: Clarifying the precise functional role of autophagy in different types of hepatotoxicity is essential for developing a type-specific autophagy-based intervention. Identification of molecular targets and novel agents for effectively and accurately manipulating autophagy is needed for better utilization of an autophagy-based approach to exert beneficial effects on hepatotoxicity. Future Directions: Well-designed clinical trials are needed to validate the efficacy of an autophagy-targeting intervention strategy for hepatotoxicity. Further studies should be also focused on developing novel autophagy-targeting agents that can accurately regulate autophagy based on the characteristics of each type of hepatotoxicity. Antioxid. Redox Signal. 38, 1082-1100.
Keywords: autophagy; functional role; hepatotoxicity; intervention; mechanisms.