文章：

GPX4在乳腺癌中的双重作用：治疗耐药机制与新型靶向治疗的潜力

The dual role of GPX4 in breast cancer: mechanisms of therapeutic resistance and potential for novel targeted therapies

原文发布日期：2025-06-24

英文摘要：

Glutathione peroxidase 4 (GPX4) is a key intracellular antioxidant enzyme that maintains oxidative homeostasis by catalyzing the reduction of lipid peroxides and relies on glutathione-specific inhibition of iron death. In recent years, it has been found that GPX4 exhibits significant aberrant expression in breast cancer (BC) and promotes BC development by regulating tumor cell proliferation, invasion, metastasis, and stem cell properties. More importantly, GPX4 overexpression leads to decreased sensitivity of BC to chemotherapy, radiotherapy, endocrine therapy, immune checkpoint inhibitors, and targeted therapies by inhibiting iron death, attenuating oxidative damage, and activating pro-survival signaling pathways. In this paper, we systematically review the molecular characterization of GPX4 and its cancer-promoting mechanism in BC, focusing on resolving its molecular regulatory network in multimodal therapy resistance. Based on the reversal of drug resistance and synergistic anti-tumor effects demonstrated by GPX4 inhibitors in preclinical studies, iron death induction strategies targeting GPX4 or combining with existing therapies are expected to be a new direction to overcome the bottleneck of drug resistance in BC.

摘要翻译：

谷胱甘肽过氧化物酶4（GPX4）是一种关键的细胞内抗氧化酶，通过催化脂质过氧化物的还原来维持氧化稳态，并依赖谷胱甘肽特异性抑制铁死亡。近年来研究发现，GPX4在乳腺癌（BC）中呈现显著异常表达，并通过调控肿瘤细胞增殖、侵袭转移和干细胞特性促进BC发展。更重要的是，GPX4过表达通过抑制铁死亡、减弱氧化损伤和激活促生存信号通路，导致BC对化疗、放疗、内分泌治疗、免疫检查点抑制剂及靶向治疗的敏感性降低。本文系统综述GPX4的分子特征及其在BC中的促癌机制，重点解析其在多模态治疗耐药中的分子调控网络。基于GPX4抑制剂在临床前研究中展现的逆转耐药和协同抗肿瘤效应，针对GPX4的铁死亡诱导策略或与现有疗法联合应用，有望成为突破BC耐药瓶颈的新方向。

原文链接：

The dual role of GPX4 in breast cancer: mechanisms of therapeutic resistance and potential for novel targeted therapies