IL6 Derived from Macrophages under Intermittent Hypoxia Exacerbates NAFLD by Promoting Ferroptosis via MARCH3‐Led Ubiquitylation of GPX4

• Published in: Advanced science 2024-11, Vol.11 (41), p.e2402241-n/a
• Main Authors: Cai, Weisong, Wu, Sa, Ming, Xiaoping, Li, Zhen, Pan, Dingyu, Yang, Xiuping, Yang, Minlan, Yuan, Yufeng, Chen, Xiong
• Format: Article
• Language: English
• Subjects: Animals; Cardiovascular disease; Cell death; Cytokines; Diabetes; Disease Models, Animal; Fatty acids; Ferroptosis; Ferroptosis - genetics; Free radicals; Humans; Hypertension; Hypoxia; Hypoxia - metabolism; IL6; Interleukin-6 - genetics; Interleukin-6 - metabolism; Iron; Lipid peroxidation; Lipids; Liver diseases; Macrophages - metabolism; Male; MARCH3; Metabolic disorders; Metabolic syndrome; Mice; Mice, Inbred C57BL; NAFLD; Non-alcoholic Fatty Liver Disease - genetics; Non-alcoholic Fatty Liver Disease - metabolism; OSA; Oxidation; Phospholipid Hydroperoxide Glutathione Peroxidase - genetics; Phospholipid Hydroperoxide Glutathione Peroxidase - metabolism; Proteins; Sleep apnea; Sleep Apnea, Obstructive - complications; Sleep Apnea, Obstructive - genetics; Sleep Apnea, Obstructive - metabolism; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Ubiquitination
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.202402241

Obstructive sleep apnea (OSA) is a common sleep disorder characterized by intermittent hypoxia (IH) and is associated with the occurrence and development of nonalcoholic fatty liver disease (NAFLD). However, the specific mechanism by which OSA induces NAFLD remains unclear. Therefore, effective interventions are lacking. This study aims to investigate the role and mechanism of ferroptosis in OSA‐related NAFLD using clinical data analyses, cell‐based molecular experiments, and animal experiments. Indicators of liver function, lipid accumulation, and ferroptosis are also examined. RNA‐seq, qPCR, western blotting, gene intervention, and E3 ligase prediction using UbiBrowser and co‐IP are used to explore the potential underlying mechanisms. The results show that ferroptosis increases in the liver tissues of patients with OSA. Chronic IH promotes NAFLD progression in mice and is alleviated by a ferroptosis inhibitor Fer‐1. The increased secretion of IL6 by macrophages can promote the expression of MARCH3 in hepatocytes under intermittent conditions, and subsequently promote the ubiquitination and degradation of GPX4 to regulate ferroptosis and lipid accumulation in hepatocytes. Hence, targeted inhibition of MARCH3 may alleviate IH‐induced ferroptosis and lipid accumulation in liver tissues and inhibit the progression of NAFLD. The study identifies that the upregulation of MARCH3 is a vital mechanism under intermittent hypoxia for IL6‐induced ubiquitination and degradation of glutathione peroxidase 4 (GPX4) in hepatocytes. Targeting the inhibition of MARCH3 can alleviate liver ferroptosis and lipid accumulation induced by intermittent hypoxia, thus slowing the progression of nonalcoholic fatty liver disease (NAFLD).