Melatonin Prevents against Ethanol-Induced Liver Injury by Mitigating Ferroptosis via Targeting Brain and Muscle ARNT-like 1 in Mice Liver and HepG2 Cells

The circadian clock acts a pivotal part in human daily physiology and metabolism. Excess alcohol consumption disturbs the circadian rhythm of several metabolism-related genes of the liver. Melatonin is a member of the foremost hormones secreted by the pineal gland with numerous pharmacological properties in quite a number of diseases. However, its potential roles and possible mechanisms in ethanol-induced ferroptosis are still not clear completely. Ethanol feeding studies were performed upon a chronic-plus-binge ethanol feeding protocol in C57BL/6 mice with or without intraperitoneal injection administration of melatonin. HepG2 cells and mice primary hepatocytes were subjected to investigation for ethanol and melatonin. The results showed that melatonin dramatically ameliorated liver injury and decreased ferroptosis makers induced by ethanol. Meanwhile, melatonin effectively reversed the circadian misalignment caused by ethanol. Additionally, melatonin accelerated Nrf2 nuclear translocation and further activated its downstream anti-ferroptosis proteins including FTH, FPN, HO-1, and SLC7A11 in ethanol-changed mice liver tissues and HepG2 cells. However, the impact of melatonin on liver protection and anti-ferroptosis was offset upon brain and muscle ARNT-like 1 (BMAL1) knockdown with the notably blocked Nrf2-ARE pathway. Altogether, this study revealed that melatonin could alleviate ethanol-induced liver injury by impeding ferroptosis via reprogramming the circadian protein BMAL1 and subsequently activating the Nrf2-ARE anti-ferroptosis pathway. The emergence of novel liver protective effects and mechanism of melatonin on ethanol-induced ferroptosis may provide a new dimension for prevention or intervention against liver injury associated with ethanol.