Melatonin Prevents the Progression of MASLD via Inhibiting FFAs-Induced Ferroptosis through KEAP1/NRF2/HO-1 Pathway

The accumulation of free fatty acids (FFAs) in hepatocytes is a key characteristic of metabolic dysfunction-associated steatotic liver disease (MASLD), which leads to lipid peroxidation and ultimately results in ferroptosis. Currently, there is an absence of efficacious therapeutic options available for the management of MASLD. Consequently, an in-depth exploration of the roles of FFAs and ferroptosis in the progression of MASLD may reveal hitherto unidentified therapeutic targets. In the study, we established an early lesion model of MASLD, namely NAFL, and comprehensive analyses of lipid metabolism, hepatocellular injury, iron homeostasis, and ferroptosis were performed. The HFD and FFAs treatment significantly elevated the expression of enzymes associated with lipid synthesis, including ACC1 and FASN, leading to enhanced lipid accumulation in hepatocytes. Additionally, HFD and FFAs resulted in increased iron loading and a reduction in the levels of the antioxidant enzyme GPX4, which ultimately triggers ferroptosis. In contrast, the administration of melatonin effectively inhibited the activity of lipid synthesis-related enzymes, decreased hepatic lipid deposition, alleviated free fatty acid-induced iron dysregulation, and mitigated liver damage. Mechanistically, melatonin has been shown to attenuate hepatocyte ferroptosis by modulating the KEAP1/NRF2/HO-1 pathway, which in turn diminishes free fatty acids-induced oxidative stress. In conclusion, melatonin alleviates MASLD progression by curbing FFAs-induced oxidative stress and ferroptosis. These findings provide valuable insights into the mechanisms underlying MASLD progression and highlight melatonin as a potential therapeutic agent for the management of MASLD.