Targeting the regulation of iron homeostasis as a potential therapeutic strategy for nonalcoholic fatty liver disease

• Published in: Metabolism, clinical and experimental clinical and experimental, 2024-08, Vol.157, p.155953, Article 155953
• Main Authors: Sui, Yutong, Geng, Xue, Wang, Ziwei, Zhang, Jing, Yang, Yanqun, Meng, Ziyu
• Format: Article
• Language: English
• Subjects: Ferroptosis; HCC; Iron homeostasis; Liver fibrosis; NAFLD; NASH
• ISSN: 0026-0495; 1532-8600; 1532-8600
• DOI: 10.1016/j.metabol.2024.155953

With aging and the increasing incidence of obesity, nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide. NAFLD mainly includes simple hepatic steatosis, nonalcoholic steatohepatitis (NASH), liver fibrosis and hepatocellular carcinoma (HCC). An imbalance in hepatic iron homeostasis is usually associated with the progression of NAFLD and induces iron overload, reactive oxygen species (ROS) production, and lipid peroxide accumulation, which leads to ferroptosis. Ferroptosis is a unique type of programmed cell death (PCD) that is characterized by iron dependence, ROS production and lipid peroxidation. The ferroptosis inhibition systems involved in NAFLD include the solute carrier family 7 member 11 (SLC7A11)/glutathione (GSH)/glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1)/coenzyme Q10 (CoQ10)/nicotinamide adenine dinucleotide phosphate (NADPH) regulatory axes. The main promotion system involved is the acyl-CoA synthetase long-chain family (ACSL4)/arachidonic lipoxygenase 15 (ALOX15) axis. In recent years, an increasing number of studies have focused on the multiple roles of iron homeostasis imbalance and ferroptosis in the progression of NAFLD. This review highlights the latest studies about iron homeostasis imbalance- and ferroptosis-associated NAFLD, mainly including the physiology and pathophysiology of hepatic iron metabolism, hepatic iron homeostasis imbalance during the development of NAFLD, and key regulatory molecules and roles of hepatic ferroptosis in NAFLD. This review aims to provide innovative therapeutic strategies for NAFLD. •Iron homeostasis imbalance participates in the progression of NAFLD.•Targeting the regulation of iron homeostasis is a therapeutic method for NAFLD•Iron overload, ROS production and lipid peroxidation trigger ferroptosis in NAFLD.