Inhibiting Ferroptosis Prevents the Progression of Steatotic Liver Disease in Obese Mice
Gi Cheol Park,
Soo-Young Bang,
Ji Min Kim,
Sung-Chan Shin,
Yong-il Cheon,
Kwang Min Kim,
Hanaro Park,
Eui-Suk Sung,
Minhyung Lee,
Jin-Choon Lee,
Byung-Joo Lee
Affiliations
Gi Cheol Park
Department of Otolaryngology—Head and Neck Surgery, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon 51353, Republic of Korea
Soo-Young Bang
Department of Otorhinolaryngology—Head and Neck Surgery, College of Medicine, Pusan National University and Biomedical Research Institute, Pusan National University Hospital, Busan 49241, Republic of Korea
Ji Min Kim
Department of Otorhinolaryngology—Head and Neck Surgery, College of Medicine, Pusan National University and Biomedical Research Institute, Pusan National University Hospital, Busan 49241, Republic of Korea
Sung-Chan Shin
Department of Otorhinolaryngology—Head and Neck Surgery, College of Medicine, Pusan National University and Biomedical Research Institute, Pusan National University Hospital, Busan 49241, Republic of Korea
Yong-il Cheon
Department of Otorhinolaryngology—Head and Neck Surgery, College of Medicine, Pusan National University and Biomedical Research Institute, Pusan National University Hospital, Busan 49241, Republic of Korea
Kwang Min Kim
Division of Gastroenterology, Department of Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon 51353, Republic of Korea
Hanaro Park
Department of Otolaryngology—Head and Neck Surgery, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon 51353, Republic of Korea
Eui-Suk Sung
Department of Otorhinolaryngology—Head and Neck Surgery, College of Medicine, Pusan National University and Biomedical Research Institute, Pusan National University Yangsan Hospital, Yangsan 50612, Republic of Korea
Minhyung Lee
Department of Otorhinolaryngology—Head and Neck Surgery, College of Medicine, Pusan National University and Biomedical Research Institute, Pusan National University Yangsan Hospital, Yangsan 50612, Republic of Korea
Jin-Choon Lee
Department of Otorhinolaryngology—Head and Neck Surgery, College of Medicine, Pusan National University and Biomedical Research Institute, Pusan National University Yangsan Hospital, Yangsan 50612, Republic of Korea
Byung-Joo Lee
Department of Otorhinolaryngology—Head and Neck Surgery, College of Medicine, Pusan National University and Biomedical Research Institute, Pusan National University Hospital, Busan 49241, Republic of Korea
Ferroptosis, a form of regulated cell death characterized by lipid peroxidation and iron accumulation, has been implicated in the progression of metabolic-dysfunction-associated steatohepatitis (MASH) in obesity. This study investigated the role of ferroptosis in the development of hepatic steatosis and MASH in obese mice and assessed the therapeutic potential of ferrostatin-1, a ferroptosis inhibitor. C57BL/6J wild-type (n = 8) and ob/ob mice (n = 16) were maintained on a standard chow diet. Mice were divided into three groups that included C57BL/6 (n = 8), ob/ob (n = 8), and ob/ob + ferrostatin-1 (FER) (n = 8), with the latter group receiving an intraperitoneal injection of 5 μM/kg ferrostatin three times per week for eight weeks. Following treatment, serum and tissue samples were collected for analysis. Significant hepatic steatosis and increased lipogenesis markers were observed in ob/ob mice, which were restored to baseline levels in the ob/ob + FER group treated with ferrostatin-1. Elevated oxidative stress was indicated by increased reactive oxygen species (ROS) and malondialdehyde (MDA) levels in the ob/ob group, while glutathione peroxidase 4 (GPX4) activity was significantly reduced. Ferrostatin-1 treatment decreases MDA levels and restores GPX4 activity. Additionally, ferrostatin mitigates iron overload and promotes macrophage polarization from M1 to M2, thereby reducing liver inflammation and fibrosis. Ferrostatin treatment reversed mitochondrial dysfunction in ob/ob mice. Our findings revealed that ferroptosis plays a significant role in the progression of obesity to hepatic steatosis and MASH. Inhibiting ferroptosis using ferrostatin-1 effectively improves liver histology, reduces oxidative stress, normalizes lipogenesis, and modulates macrophage polarization. This study highlights the potential of targeting ferroptosis as a therapeutic strategy for obesity-related liver diseases, warranting further investigation in clinical settings.
