编辑丨王多鱼 排版丨水成文 铁死亡 （ Ferroptosis ） 是 一种由铁依赖性脂质过氧化驱动的细胞程序性死亡形式， 在 过去十余年迅速 成为生物医学研究的热点。在肿瘤、神经退行性疾病和急性肾损伤等多种疾病中，铁死亡正逐渐成为具有 临床应用前景的调控通路。 然而，长期以来一个被忽视的问题是：活性氧 （ ROS） 诱导剂是否必然推动铁死亡？进一步而言，在评 估铁死亡抑制剂时，除其还原性外，是否还需要系统检验其氧化性属性？ 2026 年 1 月 27 日，暨南大学生命科学技术学院 黄俊祺 、浙江大学爱丁堡大学联合学院 Chew Ting Gang 及湛江中心人民医院 庞丽娟 、 郭允苗 作为共同通讯作者 （ 乔梦浩 、 周丽群 为论文共同第一作者 ） 在 Advanced Science 期刊发表了题为： ERM Inhibition Confers Ferroptosis Resistance through ROS-Induced NRF2 Signaling 的研究论文。 该研究揭示， ERM （ E zrin- R adixin- M oesin ） 家族蛋白是铁死亡敏感性的调控开关， ERM- 肌 ...

Core Viewpoint - The study highlights that tolerance to ferroptosis enhances lipid metabolism and pathogenic type 2 immunity in allergic airway inflammation, suggesting a potential therapeutic target for asthma through the modulation of antioxidant systems [1][6]. Group 1: Key Findings - Pathogenic ILC2 in allergic airway inflammation relies on cysteine for metabolic adaptation and survival [3]. - Cysteine uptake promotes the synthesis of glutathione (GSH), which works in conjunction with the upregulation of GPX4 and TXNRD1 to enhance resistance to ferroptosis by combating lipid peroxidation and reactive oxygen species (ROS) [3]. - The adaptive changes accelerate lipid acquisition and metabolism, promoting the expansion of ILC2 and Th2 cells [3]. Group 2: Implications - The study indicates that the antioxidant and ferroptosis resistance pathways enable lipid metabolism in ILC2 and Th2 cells [4]. - GPX4 and TXNRD1 are crucial in promoting pathogenic type 2 immune responses [4]. - The redox balance system represents a targetable metabolic vulnerability in airway inflammation [4].

Core Viewpoint - The study reveals a mechanism of liver-breast metabolic communication that drives cancer progression, particularly highlighting the role of exosomes derived from non-alcoholic fatty liver disease (NAFLD) in promoting breast cancer development [9]. Group 1: Research Findings - Exosomes from fatty liver induce the release of free fatty acids in breast adipocytes, thereby promoting breast cancer progression [3][10]. - The study establishes a correlation between NAFLD and increased breast cancer risk in atypical hyperplasia individuals, as well as poor prognosis in breast cancer patients [4]. - The accumulation of fatty liver-derived exosomes in adipocytes contributes to the formation of a pro-tumor microenvironment in the breast [4]. Group 2: Mechanisms Involved - The targeting of adipocytes by exosomes is mediated by the interaction between ErbB4 and Nrg4 [4][10]. - TRMT10C in the exosomes is transferred to mitochondria, leading to m1A modification of mitochondrial mRNA, which suppresses the translation of ND5 and ND6, resulting in increased reactive oxygen species (ROS) levels and accelerated tumor progression [4][10]. Group 3: Prognostic Indicators - Plasma ErbB4-positive exosomes are identified as an independent prognostic indicator for breast cancer patients with NAFLD [5].

Core Viewpoint - Ferroptosis is a newly discovered iron-dependent form of programmed cell death that plays a significant role in the development of various diseases, including cancer [2][4]. Group 1: Mechanism of Ferroptosis - Reactive oxygen species (ROS) are crucial in initiating lipid peroxidation and ferroptosis, significantly affecting chemotherapy resistance in cancer [3][10]. - The study published in Nature Cell Biology reveals that O-GlcNAc transferase (OGT) acts as a ROS sensor in hepatocellular carcinoma (HCC) [4][10]. - ROS-induced oxidation activates OGT, which then modifies the transcription factor FOXK2, promoting its nuclear translocation and upregulating the expression of the key gene SLC7A11, thereby inhibiting ferroptosis and enhancing chemotherapy resistance in liver cancer cells [4][8]. Group 2: Implications for Cancer Treatment - The research elucidates a ROS-mediated oxidation-O-GlcNAcylation cascade that integrates ROS signaling, O-GlcNAc modification, and FOXK2-mediated transcriptional regulation of SLC7A11, contributing to resistance against ferroptosis and chemotherapy [10]. - Targeting this mechanism may provide a novel approach to reactivate ferroptosis, offering new strategies to overcome cancer resistance [10].