Park Gi Cheol, Bang Soo-Young, Kim Ji Min, Shin Sung-Chan, Cheon Yong-Il, Kim Kwang Min, Park Hanaro, Sung Eui-Suk, Lee Minhyung, Lee Jin-Choon, Lee Byung-Joo
Department of Otolaryngology-Head and Neck Surgery, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon 51353, Republic of Korea.
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.
Antioxidants (Basel). 2024 Oct 31;13(11):1336. doi: 10.3390/antiox13111336.
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.
铁死亡是一种以脂质过氧化和铁蓄积为特征的程序性细胞死亡形式，与肥胖相关的代谢功能障碍相关脂肪性肝炎（MASH）的进展有关。本研究调查了铁死亡在肥胖小鼠肝脏脂肪变性和MASH发生发展中的作用，并评估了铁死亡抑制剂铁抑素-1的治疗潜力。C57BL/6J野生型小鼠（n = 8）和ob/ob小鼠（n = 16）维持标准饲料饮食。小鼠分为三组，包括C57BL/6（n = 8）、ob/ob（n = 8）和ob/ob + 铁抑素-1（FER）组（n = 8），后一组每周腹腔注射5 μM/kg铁抑素，共八周。治疗后，收集血清和组织样本进行分析。在ob/ob小鼠中观察到显著的肝脏脂肪变性和脂肪生成标志物增加，在用铁抑素-1治疗的ob/ob + FER组中恢复到基线水平。ob/ob组中活性氧（ROS）和丙二醛（MDA）水平升高表明氧化应激增加，而谷胱甘肽过氧化物酶4（GPX4）活性显著降低。铁抑素-1治疗可降低MDA水平并恢复GPX4活性。此外，铁抑素减轻铁过载并促进巨噬细胞从M1向M2极化，从而减轻肝脏炎症和纤维化。铁抑素治疗逆转了ob/ob小鼠的线粒体功能障碍。我们的研究结果表明，铁死亡在肥胖向肝脏脂肪变性和MASH的进展中起重要作用。使用铁抑素-1抑制铁死亡可有效改善肝脏组织学，降低氧化应激，使脂肪生成正常化，并调节巨噬细胞极化。本研究强调了将铁死亡作为肥胖相关肝病治疗策略的潜力，值得在临床环境中进一步研究。
