Hino Keisuke, Nishina Sohji, Yanatori Izumi
Digestive Disease Center, Shunan Memorial Hospital, 1-10-1 Ikunoya-Minami, Kudamatsu, Yamaguchi, 744-0033, Japan.
Department of Gastroenterology and Hepatology, Kawasaki Medical School, Kurashiki, Japan.
J Gastroenterol. 2025 Sep 18. doi: 10.1007/s00535-025-02300-5.
Ferroptosis is a form of nonapoptotic cell death that is driven by iron-dependent lipid peroxidation and is relevant to a wide range of biological processes, such as development, aging, immunity, and cancer. Ferroptosis has also been linked to numerous hepatic metabolic pathways, including the metabolism of iron, fatty acids, and amino acids, such as cysteine. During the last decade, studies on the biology of and molecules regulating ferroptosis have shed light on the role of ferroptosis in liver disease and its implications. The susceptibility of liver cells to ferroptosis determines the extent of liver injury and affects the progression of nonneoplastic diseases, whereas liver cancer cells display intrinsic or acquired resistance to ferroptosis, which promotes cancer progression. These findings indicate that ferroptosis represents a promising target for the prevention and treatment of many forms of liver disease. In this review, we provide an update on the mechanisms regulating ferroptosis, focusing on the peroxidation of phospholipids, the antioxidant pathways that limit lipid peroxidation, and the regulation of the labile iron pool, all of which are closely connected. We also summarize the roles and importance of ferroptosis in the pathogenesis of liver disease, and the therapeutic potential of targeting ferroptosis in liver diseases.
铁死亡是一种非凋亡性细胞死亡形式，由铁依赖性脂质过氧化驱动，与多种生物学过程相关，如发育、衰老、免疫和癌症。铁死亡还与众多肝脏代谢途径有关，包括铁、脂肪酸和氨基酸（如半胱氨酸）的代谢。在过去十年中，关于铁死亡生物学和调节铁死亡分子的研究揭示了铁死亡在肝脏疾病中的作用及其影响。肝细胞对铁死亡的易感性决定了肝损伤的程度，并影响非肿瘤性疾病的进展，而肝癌细胞对铁死亡表现出内在或获得性抗性，这促进了癌症进展。这些发现表明，铁死亡是预防和治疗多种肝脏疾病的一个有前景的靶点。在本综述中，我们提供了关于调节铁死亡机制的最新进展，重点关注磷脂的过氧化、限制脂质过氧化的抗氧化途径以及不稳定铁池的调节，所有这些都紧密相连。我们还总结了铁死亡在肝脏疾病发病机制中的作用和重要性，以及针对肝脏疾病靶向铁死亡的治疗潜力。
