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HIFs-PHDs氧传感途径在细胞铁死亡中的作用研究进展

周结, 李芳^*, 朱薛羽, 沈海俊, 陆荣柱

江苏大学医学院预防医学与卫生检验系，镇江 212013

摘要

缺氧诱导因子(hypoxia-inducible factors, HIFs)是调节氧平衡的主要转录因子之一，其稳定性由对氧敏感的脯氨酸羟化酶结构域(prolyl hydroxylase domain, PHD)的羟化状态决定。近年来已有研究表明，HIFs-脯氨酸羟化酶(prolyl hydroxylases, PHDs)氧传感途径参与细胞铁死亡(ferroptosis)的过程。铁死亡是近年来发现的一种不同于坏死、凋亡、坏死性凋亡和焦亡等的新型细胞死亡方式，其本质是细胞内铁依赖的脂质过氧化物蓄积引起的程序性死亡方式。本文从与铁死亡相关的铁代谢、脂代谢和谷胱甘肽(glutathione, GSH)合成/代谢三方面重点论述HIFs-PHDs氧传感途径在神经疾病、肿瘤、肺损伤及化学性神经损伤相关的细胞铁死亡中的作用及其机制的研究进展，为开发靶向HIFs-PHDs氧传感途径的铁死亡调节剂治疗神经系统疾病、肿瘤等与铁死亡相关疾病提供理论依据及新思路。

关键词： 缺氧诱导因子; 脯氨酸羟化酶; 铁死亡; 铁代谢; 脂质活性氧

分类号：R34

Research progress on the role of HIFs-PHDs oxygen-sensing pathway in cellular ferroptosis

ZHOU Jie, LI Fang^*, ZHU Xue-Yu, SHEN Hai-Jun, LU Rong-Zhu

Department of Preventive Medicine and Public Health Laboratory Sciences, School of Medicine, Jiangsu University, Zhenjiang 212013, China

Abstract

Hypoxia-inducible factors (HIFs) are one of the primary transcription factors regulating oxygen balance, and their stability is determined by the hydroxylation state of the prolyl hydroxylase domain (PHD) that is sensitive to oxygen. In recent years, studies have shown that HIFs-prolyl hydroxylases (PHDs) oxygen-sensing pathway is involved in the process of cellular ferroptosis. Ferroptosis, a new type of cell death, different from necrosis, apoptosis, necrotizing apoptosis, and pyroptosis, is essentially a programmed death caused by the accumulation of iron-dependent lipid peroxides in cells. This paper focuses on the role and mechanism of the HIFs-PHDs oxygen-sensing pathway in cellular ferroptosis involved in nerve diseases, tumors, lung injury, and chemical nerve damage from three aspects of iron metabolism, lipid metabolism, and glutathione (GSH) synthesis/metabolism. This review will provide a theoretical basis and new ideas for the development of novel drugs targeting the HIFs-PHDs oxygen-sensing pathway and capable of regulating ferroptosis for the treatment of diseases related to ferroptosis such as nervous system diseases and tumors.

Key words: hypoxia-inducible factors; prolyl hydroxylase; ferroptosis; iron metabolism; lipid reactive oxygen species

收稿日期：2020-12-28　　录用日期：2021-06-03

通讯作者：李芳　　E-mail: lfsjy@ujs.edu.cn

引用本文：

周结, 李芳, 朱薛羽, 沈海俊, 陆荣柱. HIFs-PHDs氧传感途径在细胞铁死亡中的作用研究进展[J]. 生理学报 2021; 73 (6): 1017-1024.

ZHOU Jie, LI Fang, ZHU Xue-Yu, SHEN Hai-Jun, LU Rong-Zhu. Research progress on the role of HIFs-PHDs oxygen-sensing pathway in cellular ferroptosis. Acta Physiol Sin 2021; 73 (6): 1017-1024 (in Chinese with English abstract).