《生命科学》 2026, 38(10): 1754-1764

铁过载导致的铁死亡在胶质母细胞瘤中的作用机制及治疗前景

张浩洁^1,2 , 王晨^1,2 , 廖智鹏^1,2 , 张子涵^1,2 , 潘亚文^1,2,3,*

¹兰州大学第二临床医学院，兰州 730030 ²兰州大学第二医院神经病学研究所，兰州 730030 ³兰州大学第二医院神经外科，兰州 730030

摘　要：

胶质母细胞瘤（glioblastoma， GBM）是中枢神经系统最具侵袭性的恶性肿瘤。GBM表现出显著的铁过载特征，这种代谢异常不仅支持肿瘤快速增殖，也使其对铁依赖性程序性细胞死亡——铁死亡具有潜在敏感性。本文系统综述了GBM中铁过载与铁死亡调控机制之间的复杂关联，重点探讨了GBM中NCOA4-铁蛋白自噬、SLC7A11-GPX4、Nrf2-Keap1 等关键通路在调控铁死亡中的作用；在此基础上，总结了基于铁过载与铁死亡的治疗策略，包括小分子药物、纳米载体系统、信号通路抑制剂及免疫微环境调节等新型干预手段，旨在将GBM固有的铁过载特性转化为治疗突破口。

通讯作者：潘亚文 , Email:pyw@lzu.edu.cn

Mechanisms and therapeutic prospects of iron overload-induced ferroptosis in glioblastoma

ZHANG Hao-Jie^1,2 , WANG Chen^1,2 , LIAO Zhi-Peng^1,2 , ZHANG Zi-Han^1,2 , PAN Ya-Wen^1,2,3,*

¹The Second Medical College of Lanzhou University, Lanzhou 730030, China ²Institute of Neurology, The Second Hospital of Lanzhou University, Lanzhou 730030, China ³Department of Neurosurgery, The Second Hospital of Lanzhou University, Lanzhou 730030, China

Abstract:

Glioblastoma (GBM) is the most aggressive primary malignant tumor of the central nervous system, characterized by profound therapeutic resistance and high recurrence rate, which pose significant clinical challenges. Recent studies have revealed that GBM cells display a distinctive metabolic profile marked by substantial iron accumulation. This dysregulated iron homeostasis not only supplies essential enzymatic cofactors and fulfills the bioenergetic demands of rapid tumor proliferation, but also sensitizes GBM cells to ferroptosis, an iron-dependent form of regulated cell death driven by lethal lipid peroxidation. This process, in turn, represents a potential metabolic vulnerability. This review systematically delineates the complex interplay between iron overload and ferroptosis regulatory mechanisms in GBM. The mechanistic framework is organized into three functional modules: aberrant iron metabolism, lipid peroxidation execution, and multi-layered defense mechanisms. We focus on critical regulatory nodes, including TFR1/DMT1-mediated iron uptake, NCOA4-mediated ferritinophagy, and antioxidant defense networks, such as the System Xc-/GPX4 axis, Nrf2-Keap1 signaling and FSP1. Building on these mechanistic insights, we summarize innovative therapeutic strategies targeting the iron-overload phenotype of GBM. These strategies include potent small-molecule inducers, smart nanoplatforms capable of crossing the blood-brain barrier (BBB), targeted signaling pathway inhibitors, and synergistic interventions that combine ferroptosis induction with immune microenvironment modulation. By integrating current mechanistic and translational research, this review provides a conceptual framework and forward-looking perspectives for the development of novel precision therapies that exploit the intrinsic metabolic hallmarks of GBM to improve patient outcomes.

Communication Author：PAN Ya-Wen , Email:pyw@lzu.edu.cn