铁死亡在肝癌发生发展与治疗中的作用：机制、靶向策略及转化前景

The role of ferroptosis in the initiation, progression, and treatment of liver cancer: mechanisms, targeted strategies, and translational perspectives

摘要:

铁死亡是一种铁依赖性脂质过氧化驱动的程序性细胞死亡方式，在肝癌发生发展及治疗抵抗中发挥重要作用。近年来，围绕铁死亡调控网络的基础与转化研究不断深入。本文系统梳理铁死亡在肝癌中的分子机制、亚型异质性特征及其与肿瘤微环境的相互作用，重点总结系统Xc^--GSH-GPX4轴、铁代谢失衡及脂质重塑通路在肝癌铁死亡调控中的核心地位。在治疗层面，铁死亡诱导剂单药及其与化疗、靶向治疗、免疫治疗和放疗的联合策略显示出协同抗肿瘤潜力，部分方案已进入早期临床探索阶段。此外，长链脂酰辅酶A合成酶4、法尼基二磷酸法尼基转移酶1等铁死亡相关标志物在预后分层及疗效预测中的应用价值逐渐显现。未来仍需进一步阐明铁死亡与肿瘤微环境的动态互作机制，完善生物标志物体系，并优化临床试验设计，以推动铁死亡靶向策略在肝癌精准治疗中的转化应用。

Abstract:

Ferroptosis is an iron-dependent form of programmed cell death driven by lipid peroxidation and plays a critical role in the initiation, progression, and therapeutic resistance of liver cancer. In recent years, both basic and translational studies focusing on the regulatory network of ferroptosis have advanced substantially. This article systematically reviews the molecular mechanisms of ferroptosis in liver cancer, its subtype heterogeneity, and its interactions with the tumor microenvironment. Particular emphasis is placed on the central roles of the system Xc^--GSH-GPX4 axis, dysregulated iron metabolism, and lipid remodeling pathways in ferroptosis regulation in liver cancer. From a therapeutic perspective, ferroptosis inducers, either as monotherapy or in combination with chemotherapy, targeted therapy, immunotherapy, and radiotherapy, have demonstrated synergistic antitumor potential, with some strategies entering early-phase clinical evaluation. In addition, ferroptosis-related biomarkers, such as ACSL4 and FDFT1, are increasingly recognized for their value in prognostic stratification and treatment response prediction. Further studies are warranted to elucidate the dynamic interplay between ferroptosis and the tumor microenvironment, refine biomarker systems, and optimize clinical trial design, thereby accelerating the translational application of ferroptosis-targeted strategies in precision therapy for liver cancer.