Autophagy in the liver

The liver plays a dynamic role in maintaining whole-body homeostasis through its control of nutrient metabolism, detoxification, and immune regulation. Autophagy, a conserved lysosomal degradation pathway, is central to these functions, enabling hepatocytes to adapt to fluctuations in nutrient availability, hormonal signals, and cellular stress. Hepatic autophagy is tightly regulated by nutrient and energy-sensing pathways, including AMPK, mTOR, the coordinated actions of insulin and glucagon, and transcriptional regulators TFEB, FOXO proteins, PPAR isoforms, FXR, and NRF2. Epigenomic mechanisms, chromatin remodeling complexes, and post-transcriptional regulators, such as microRNAs (miRNAs), RNA-binding proteins (RBPs), and liquid-liquid phase separation (LLPS), further refine autophagy gene expression and autophagosome formation. In physiological conditions, autophagy maintains hepatocyte integrity by supporting lipid, carbohydrate, and protein turnover and by clearing damaged or excess organelles through selective pathways such as mitophagy, lipophagy, pexophagy, ER-phagy, and xenophagy. Autophagy dysfunction contributes to the development of various liver diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-associated liver disease (ALD), cholestatic liver disease, liver fibrosis, and hepatocellular carcinoma (HCC). Understanding the diverse regulatory networks governing hepatic autophagy, along with the roles of autophagy in liver homeostasis, provides new opportunities for therapeutic intervention. This review summarizes existing findings on the role of autophagy in the liver, focusing on recent advances in the regulation of hepatic autophagy. It also highlights unresolved mechanisms and discusses how targeting autophagy may offer novel strategies for treating liver diseases.