Matsumoto Takashi, Nita Akihiro, Kanamori Yohei, Maeda Ayato, Nita Tomomi, Yasuda-Yoshihara Noriko, Mima Kosuke, Okabe Hirohisa, Imai Katsunori, Hayashi Hiromitsu, Matsuoka Yuta, Nagaoka Katsuya, Nakayama Keiichi I, Sugiura Yuki, Tanaka Yasuhito, Baba Hideo, Moroishi Toshiro
Department of Molecular and Medical Pharmacology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Hepatol Commun. 2025 May 29;9(6). doi: 10.1097/HC9.0000000000000721. eCollection 2025 Jun 1.
Ferroptosis, a distinctive form of cell death induced by iron-dependent lipid peroxidation, is implicated in various biological processes, including liver diseases. Establishing an iron overload-induced ferroptosis model and identifying hepatic gene signatures associated with ferroptosis are crucial for understanding its role in liver pathogenesis.
F-box and leucine-rich repeat protein 5 (FBXL5) is a substrate-recognition component of the SCF E3 ligase complex that restricts intracellular iron levels. In this study, we used liver-specific Fbxl5-null mice to establish an iron overload-induced ferroptosis model. Transcriptome analysis identified genes involved in hepatic ferroptosis. Integrating these gene signatures with another ferroptosis model enabled the assessment of ferroptosis-related pathology in murine liver injury models and in 174 patients undergoing liver resection surgery.
Iron overload induced severe liver damage in liver-specific Fbxl5-null mice, characterized by elevated liver enzymes, histopathological changes, and lipid peroxidation. Transcriptome analysis revealed a distinct set of genes associated with hepatic ferroptosis response. Generating a gene signature for evaluating ferroptosis enhanced the understanding of ferroptosis-related pathologies in liver diseases. Iron overload exacerbated liver damage in murine ischemia-reperfusion injury models via ferroptosis induction. In human patients, elevated serum iron levels correlated with sustained postoperative liver damage, indicating heightened susceptibility to ferroptosis.
Here, a murine model of iron overload-induced hepatic ferroptosis was established, and a gene signature indicative of hepatic ferroptosis response in both mice and humans was identified. These findings underscore the role of ferroptosis in liver injury progression and suggest potential therapeutic targets for liver disease intervention.
铁死亡是一种由铁依赖性脂质过氧化诱导的独特细胞死亡形式，与包括肝脏疾病在内的各种生物学过程有关。建立铁过载诱导的铁死亡模型并鉴定与铁死亡相关的肝脏基因特征对于理解其在肝脏发病机制中的作用至关重要。
F-盒和富含亮氨酸重复蛋白5（FBXL5）是限制细胞内铁水平的SCF E3连接酶复合物的底物识别成分。在本研究中，我们使用肝脏特异性Fbxl5基因敲除小鼠建立铁过载诱导的铁死亡模型。转录组分析确定了参与肝脏铁死亡的基因。将这些基因特征与另一个铁死亡模型相结合，能够评估小鼠肝损伤模型和174例接受肝切除手术患者中铁死亡相关的病理学。
铁过载在肝脏特异性Fbxl5基因敲除小鼠中诱导了严重的肝损伤，其特征为肝酶升高、组织病理学改变和脂质过氧化。转录组分析揭示了一组与肝脏铁死亡反应相关的独特基因。生成用于评估铁死亡的基因特征增强了对肝脏疾病中铁死亡相关病理学的理解。铁过载通过诱导铁死亡加剧了小鼠缺血再灌注损伤模型中的肝损伤。在人类患者中，血清铁水平升高与术后持续性肝损伤相关，表明对铁死亡的易感性增加。
在此，建立了铁过载诱导的肝脏铁死亡小鼠模型，并鉴定了在小鼠和人类中均指示肝脏铁死亡反应的基因特征。这些发现强调了铁死亡在肝损伤进展中的作用，并提示了肝脏疾病干预的潜在治疗靶点。
