Molecular mechanisms of alcohol-associated liver disease-ferroptosis and autophagy crosstalk.

Abstract

Alcohol-associated liver disease (ALD) is a chronic liver injury caused by prolonged heavy drinking and its pathogenesis is extremely complex. According to current researches, ethanol metabolism and the generation of some of its related metabolites, including acetaldehyde and reactive oxygen species, are significant contributors to hepatocyte toxicity. These substances-induced lipid metabolism disorders, inflammatory response, mitochondrial damage, and cellular oxidative stress are important factors that lead to liver injury. Ethanol has been shown in numerous studies to exacerbate ALD by disrupting autophagy via a variety of mechanisms. ALD can be somewhat alleviated by activating autophagy, which plays a significant role in the development of ALD by removing accumulated protein polymers, damaged mitochondria, and excess lipid droplets from hepatocytes. Furthermore, persistent alcohol use raises serum iron levels, which in turn causes hepatocytes to absorb more iron. This, in turn, encourages iron loading in the liver's and other organs' parenchymal and nonparenchymal cells, finally resulting in ferroptosis. Both ferroptosis and autophagy are significant types of controlled cell death, and new research has revealed that cellular autophagy and a variety of signaling pathways play a key role in the initiation and progression of ferroptosis. Alcohol and iron both have the ability to cause oxidative stress on their own, thus their combined effects hasten liver damage. Iron loading, on the other hand, accelerates the development of ALD by triggering mitochondrial oxidative stress and activating signaling pathways and proteins linked to Ferritinophagy. Thus, we think that a new approach to treating ALD in the future will involve examining the interaction between ferroptosis and mitochondrial autophagy based on iron overload.