编译丨王聪 编辑丨王多鱼 排版丨水成文 铁死亡 （ ferroptosis ）是一种以铁依赖的脂质过氧化为特征的受调控细胞死亡形式，因其在肿瘤治疗中的潜力而备受关注。尽管铁死亡的生物学机制已得到广 泛研究，但其抗肿瘤效果仍受到显著限制。复杂的生物环境给铁死亡诱导剂向肿瘤组织的精准递送带来了挑战。然而，纳米技术的最新进展为肿瘤铁死亡的革新 提供了新的视角。 2025 年 10 月 3 日，深圳大学 黄鹏 、 林静 等在 Cell 子刊 Cell Biomaterials 上发表了题为： Nanotechnology for tumor ferroptosis 的综述论文。 该综述系统总结了 铁死亡生物学机制 与 铁死亡纳米材料设计 之间的关系，特别强调了 纳米药物递送系统 （NDDS） 如何调控多种分子途径、破坏细胞器功能 以及提高肿瘤特异性递送。该综述将为设计先进的 NDDS 以递送铁死亡诱导剂提供了宝贵见解，并有助于促进下一代肿瘤铁死亡创新策略的发展。 癌症 是全球主要的健康挑战，是导致死亡的主要原因之一。尽管化疗和放疗等传统疗法已被广泛用于癌症治疗，但这些基于细胞凋亡的治疗策略存在固有的缺 陷。例如癌细胞 ...

撰文丨王聪 编辑丨王多鱼 排版丨水成文 肺癌 是一种极为常见的恶性肿瘤，是全球癌症相关死亡的主要原因。值得注意的是， 非小细胞肺癌 （NSCLC） 约占所有肺癌病例的 85%，其中 肺腺癌 （LUAD） 是最常见的亚型。尽管癌症治疗方面近来有所进展，但肺腺癌患者的预后仍然不佳，五年生存率低于 26%。 乳酸化修饰 （ lactylation ） 是一种由 乳酸 （LA） 介导的蛋白质翻译后修饰，因其在表观遗传调控中的关键作用而备受关注。然而，乳酸化修饰与 铁死亡 在 肺腺癌 （LUAD） 中的复杂相互作用，仍有待全面阐明。 2025 年 10 月 7 日，复旦大学附属中山医院 詹成 、 范虹 、 Bi Guoshu 等人在 Cell Discovery 期刊发表了题为 ： Ferroptosis-induced SUMO2 lactylation counteracts ferroptosis by enhancing ACSL4 degradation in lung adenocarcinoma 的研究论文。 该研究表明， 铁死亡 诱导的 SUMO2 乳酸化修饰 ，通过增强 肺腺癌 中 ACSL4 的降解 ...

Core Insights - Cell ferroptosis has been confirmed to be related to the development of various liver diseases [1] - A new study from Japan indicates that two volatile molecules produced during ferroptosis can be detected in the breath of patients [1] Group 1: Research Findings - Ferroptosis is a specific type of programmed cell death characterized by abnormal accumulation of iron ions and lipid peroxidation [1] - The main pathological process of ferroptosis involves irreversible damage to cell membrane structures due to lipid peroxidation, leading to loss of cell function [1] - Current detection methods for ferroptosis primarily rely on invasive tissue biopsies, which impose significant burdens on patients [1] Group 2: Methodology and Implications - Researchers from Kyoto University and other institutions utilized a newly developed oxidative volatile organic compound analysis technique to study volatile molecules released during ferroptosis [1] - The study identified two "iron-smelling molecules" that increase in concentration as ferroptosis progresses [1] - These molecules were found to be elevated in both the liver and breath of liver disease model mice, as well as in the breath of liver disease patients [1] Group 3: Future Applications - Based on the research findings, alternative methods to liver biopsy could be developed for health diagnostics and monitoring the progression of liver diseases [2] - The research results have been published in the journal "Redox Biology" [2]

Core Viewpoint - Immunotherapy, particularly immune checkpoint blockade (ICB), presents transformative potential for treating various malignancies, but challenges such as acquired resistance and immune-related adverse events (irAEs) persist, necessitating a dual approach to address both thromboembolic risks and treatment resistance [2][5]. Group 1: Research Findings - A study published in Cell Reports Medicine indicates that the antiplatelet drug Vorapaxar enhances mitochondria-associated ferroptosis, thereby improving cancer immunotherapy outcomes by targeting the FOXO1/HMOX1 axis [3][6]. - Vorapaxar, approved by the FDA in 2014, reversibly inhibits the PAR-1 receptor on platelets, blocking thrombin-mediated platelet activation, which is crucial for antithrombotic therapy [6]. - The study confirms that Vorapaxar binds to FOXO1, inhibiting its phosphorylation and promoting its nuclear translocation, leading to increased expression of heme oxygenase-1 (HMOX1) and subsequent mitochondrial iron overload and ferroptosis [6]. Group 2: Clinical Implications - Vorapaxar has been shown to enhance immune therapy-induced tumor ferroptosis and antitumor immunity in various melanoma mouse models, suggesting its potential as a powerful adjunct in immunotherapy [6][8]. - High co-expression of FOXO1/HMOX1 is associated with improved responses to immunotherapy and prolonged progression-free survival, indicating a promising biomarker for treatment efficacy [6][8]. - Overall, Vorapaxar is positioned as a dual-benefit solution for cancer patients requiring both thrombolytic and immunotherapeutic interventions, addressing the dual challenges of thromboembolism and treatment resistance [8].

Core Viewpoint - The study reveals that HEBP2-mediated glutamine competition between tumor cells and macrophages dictates the efficacy of immunotherapy in triple-negative breast cancer (TNBC), identifying GSTP1 as a new therapeutic target to enhance treatment outcomes [3][4]. Group 1: Research Findings - The research team developed a single-cell RNA sequencing (scRNA-seq) immune therapy cohort (N=27) and a spatial transcriptomics cohort (N=88) to elucidate the metabolic interactions related to TNBC treatment efficacy [5]. - High expression of HEBP2 in tumor cells, characterized by active glutathione metabolism, and CCL3+ macrophages, characterized by oxidative metabolism, indicate effective immunotherapy, showing a negative correlation in quantity and spatial distribution [5]. - HEBP2 disrupts the cytoplasmic phase separation of the transcription factor FOXA1, promoting its nuclear translocation, which upregulates GSTP1 expression and glutamine consumption in tumor cells [5][6]. Group 2: Implications for Treatment - The metabolic shift induced by HEBP2 leads to ferroptosis in CCL3+ macrophages, impairing anti-tumor immunity [5]. - The use of GSTP1 inhibitors (Ezatiostat) can block this pathway, preventing excessive glutamine consumption by tumor cells, thereby protecting macrophages and restoring anti-tumor immunity, making TNBC more sensitive to cancer immunotherapy (anti-PD-1 monoclonal antibodies) [5][7]. - The findings establish a metabolic checkpoint regulated by the HEBP2/GSTP1 signaling axis, pioneering the assessment of immune metabolic weaknesses at the single-cell level [6][7].

Core Viewpoint - The research reveals the critical role of endocytosis in cysteine-deprivation-induced ferroptosis, challenging previous understandings of lysosomal inhibitor mechanisms and suggesting different execution pathways for ferroptosis [3][7]. Group 1: Key Findings - Lysosomal inhibitors can independently suppress cysteine-deprivation-induced (CDI) ferroptosis, regardless of autophagy [5]. - Endocytosis is essential for CDI ferroptosis but is not required for ferroptosis induced by GPX4 depletion [5]. - Endocytic defects reduce intracellular iron levels and prevent CDI ferroptosis [5]. Group 2: Mechanisms and Implications - Transferrin's clathrin-mediated endocytosis (CME) is crucial for driving CDI ferroptosis [4][5]. - Inhibition of lysosomal proteolytic activity does not prevent ferroptosis, while disrupting endosomal acidification and removing endocytic protein AP2M1 can block ferroptosis [4]. - Supplementing iron through ammonium iron citrate, independent of endocytosis, can restore CDI ferroptosis in cells with endocytic defects [4].

Core Viewpoint - The study published in Nature reveals that estrogen can inhibit ferroptosis and acute kidney injury (AKI), providing insights into the gender differences observed in AKI susceptibility, with men and postmenopausal women being more prone to this condition compared to premenopausal women [2][4][6]. Summary by Sections Gender Differences in AKI - Research indicates that men have a higher incidence and mortality rate from AKI compared to women, particularly when comparing to premenopausal women [4]. - The study suggests that this gender difference may be linked to the sensitivity of acute tubular necrosis (ATN) to ferroptosis, a major type of cell death in AKI [4]. Role of Estrogen - The research focuses on the protective role of estrogen against ferroptosis, demonstrating that estrogen can significantly inhibit cell death mediated by ferroptosis in female renal tubules [4][6]. - Estrogen, specifically 17β-estradiol, establishes an anti-ferroptotic state through both genomic and non-genomic mechanisms, including: - Direct inhibition of ferroptosis by hydroxylated estrogen derivatives, which act as free radical scavengers [4]. - The FSP1-mediated regeneration of oxidized hydroxylated estrogen, indicating a complex interplay in the protective mechanisms [4]. - Regulation by estrogen receptor ESR1, which enhances the anti-ferroptotic capacity of renal tubules [4][6]. Implications for Kidney Protection - The findings elucidate the mechanisms by which female renal tubules resist ferroptosis, explaining the increased susceptibility to AKI in men and postmenopausal women due to decreased estrogen levels [6]. - This research suggests potential therapeutic approaches for kidney protection in males and postmenopausal females, such as the use of estrogen metabolites or ferroptosis inhibitors [6]. - The study emphasizes the importance of gender as a biological variable in the regulation of ferroptosis, with broader implications beyond kidney diseases, potentially affecting conditions like heart disease and stroke [6].

Core Viewpoint - The study reveals that hypoxia inhibits ferroptosis through a HIF-independent mechanism by suppressing KDM6A, a key player in lipid metabolism and ferroptosis resistance [2][5]. Group 1: Mechanism of Ferroptosis Regulation - Long-term hypoxia can inhibit ferroptosis in a HIF-independent manner [5]. - Hypoxia suppresses KDM6A, reshaping the lipid profile to confer resistance to ferroptosis [3][5]. - KDM6A acts as a non-classical oxygen sensor in the ferroptosis process, indicating a novel regulatory pathway [2][5]. Group 2: Implications for Cancer - The loss of KDM6A, a tumor suppressor, is commonly observed in bladder cancer, leading to resistance to ferroptosis [5]. - Pharmacological inhibition of EZH2, which opposes KDM6A activity, restores sensitivity to ferroptosis in bladder tumors carrying KDM6A mutations [4][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].

Core Viewpoint - Ferroptosis is a newly regulated form of programmed cell death closely related to various liver diseases, with a lack of specific covalent inhibitors targeting ferroptosis [2][3]. Group 1: Research Findings - The research team identified Rociletinib (ROC), an EGFR inhibitor in clinical trials, as a potent ferroptosis inhibitor through virtual screening and mechanistic studies [4]. - ROC covalently binds to the 170th cysteine of the ACSL4 protein, inhibiting its enzymatic activity, thereby suppressing lipid peroxidation and subsequent ferroptosis [5][8]. - ROC effectively alleviates acute liver injury mediated by ferroptosis in mouse models, establishing it as a promising therapeutic strategy for ferroptosis-related diseases [7][8]. Group 2: Target and Mechanism - ACSL4 is a key enzyme in lipid metabolism and its abnormal activation leads to ferroptosis, making it an important therapeutic target for ferroptosis-related diseases [3]. - The study highlights ROC as a direct covalent inhibitor targeting ACSL4, providing a new avenue for treatment [7].