Core Viewpoint - Ferroptosis is emerging as a promising anti-tumor therapy driven by the oxidation of polyunsaturated fatty acids in cell membranes, leading to lipid peroxidation and cell death, while also releasing damage-associated molecular patterns (DAMPs) that enhance T cell activation [1][4]. Summary by Sections Ferroptosis Mechanism and Challenges - Ferroptosis induces cell death through increased intracellular iron, reduced glutathione synthesis, and elevated reactive oxygen species (ROS) levels. However, the upregulation of PD-L1 in tumor cells can inhibit cytotoxic T cell recognition, leading to immune suppression [1][5]. Research Development - A team from Shenyang Pharmaceutical University and Shenzhen University developed a fluorinated prodrug-engineered nano-remodeler that combines a PD-L1 inhibitor (JQ1) and a ferroptosis inducer (sorafenib) to enhance oxygen supply in hypoxic tumors, significantly improving the efficacy of ferroptosis and anti-tumor immunogenicity [2][6]. Nano-remodeler Characteristics - The engineered nano-remodeler (FJSO NA) has high oxygen solubility and releases oxygen in low-pressure environments, alleviating hypoxia in solid tumors, downregulating PD-L1 expression, and enhancing ferroptosis induction and anti-tumor immune responses [6][8]. Efficacy and Safety - The study demonstrated that the nano-remodeler effectively inhibited tumor growth in various models without significant toxicity, indicating a promising direction for enhancing ferroptosis-based immunotherapy by addressing the hypoxic tumor microenvironment [8].

撰文丨王聪 编辑丨王多鱼 排版丨水成文 铁死亡 （Ferroptosis） 是 2012 年由哥伦比亚大学 Brent Stockwell 实验室发现的一种铁依赖性的新型细胞程序性死亡方式，由过度堆积的 过氧化脂质 （peroxidized lipids） 诱导发生，其形态特征，作用方式以及分子机制与其他程序性死亡方式截然不同。同时，细胞中存在多个对抗铁死亡的防御途径，例如 谷 胱甘肽过氧化物酶 4 （GPX4） 通过 谷胱甘肽 （GSH） 特异性催化过氧化脂质来抑制铁死亡的发生； FSP1 通过产生 辅酶 Q10 （CoQ10） 的抗氧化形式促 进癌细胞对铁死亡的抵抗。 近年来的研究表明， 铁死亡在 癌症 等多种疾病发生发展中扮演着重要角色。此外， 免疫治疗或放射治疗可诱导肿瘤细胞铁死亡，且铁死亡在肿瘤免疫治疗及放 疗的疗效发挥中发挥着重要的促进作用。 尽管研究人员普遍热衷于将铁死亡作为一种新的抗癌策略加以利用，但铁死亡是否是肿瘤发生的障碍，以及能否在治疗上加以利用，目前仍不得而知。 靶向 FSP1，引发肺癌铁死亡 2025 年 11 月 5 日， 纽约大学格罗斯曼医学院的研究人员在 Nature 期刊发表 ...

Core Viewpoint - Systemic treatment is the best option for patients with unresectable or advanced hepatocellular carcinoma (HCC), but its efficacy is limited by drug resistance [2][3]. Group 1: Research Findings - Ferroptosis is a unique form of regulated cell death that plays a crucial role in the systemic treatment of HCC [3]. - A study published in Nature Cancer reveals that SCRN1 confers resistance to ferroptosis in HCC by stabilizing GPX4 through STK38-mediated phosphorylation, providing potential therapeutic targets and strategies for HCC treatment [4][8]. - The research team found that high expression of SCRN1 is closely related to ferroptosis resistance and poor prognosis in HCC [7]. Group 2: Mechanism of Action - SCRN1 enhances the interaction between STK38 and GPX4, promoting the phosphorylation of GPX4 at the S45 site, which impairs HSC70's recognition of GPX4 and reduces its degradation via chaperone-mediated autophagy, thereby alleviating lipid peroxidation and ferroptosis [7][8].

Core Viewpoint - The article discusses the emerging focus on metabolic cell death as a new frontier in cancer therapy, highlighting the significance of ferroptosis, cuproptosis, and disulfidptosis as potential therapeutic targets against cancer cells that evade traditional cell death pathways [3][4][5]. Group 1: Metabolic Cell Death Mechanisms - Metabolic cell death is characterized by the collapse of metabolic homeostasis, leading to irreversible cell death due to nutrient deprivation or the accumulation of harmful metabolites [3]. - Ferroptosis, discovered in 2012, is an iron-dependent cell death mechanism that results from uncontrolled lipid peroxidation, leading to membrane damage [8]. - Cuproptosis, identified in 2022, is a copper-dependent cell death mechanism where excess copper ions induce protein toxicity by binding to fatty acylated proteins in mitochondria [14]. - Disulfidptosis, proposed in 2023, occurs when cystine accumulation leads to the collapse of the actin cytoskeleton under conditions of glucose deprivation or NADPH depletion [19]. Group 2: Cancer Treatment Implications - Targeting metabolic cell death pathways presents a unique opportunity to exploit cancer cells' vulnerabilities, particularly through the mechanisms of ferroptosis, cuproptosis, and disulfidptosis [5][26]. - The interplay between these pathways suggests that combined interventions could enhance therapeutic efficacy and overcome drug resistance in cancer treatment [24][26]. - Establishing verifiable biomarker systems is crucial for advancing clinical applications and achieving precise patient stratification and treatment [26].

Core Insights - Ferroptosis is a regulated form of cell death characterized by iron-dependent lipid peroxidation, gaining attention for its potential in cancer therapy [2][6] - Despite extensive research on the biological mechanisms of ferroptosis, its anti-tumor effects are significantly limited due to challenges in the precise delivery of ferroptosis inducers to tumor tissues [2][4] Group 1: Biological Mechanisms and Challenges - Cancer remains a major global health challenge and a leading cause of death, with traditional therapies like chemotherapy and radiotherapy facing inherent limitations such as drug resistance and reduced efficacy in hypoxic tumor microenvironments [6] - Ferroptosis, first reported in 2012, offers a promising opportunity to overcome clinical bottlenecks faced by traditional cancer therapies, with its therapeutic effects validated in various cancer types including pancreatic ductal adenocarcinoma, hepatocellular carcinoma, renal cell carcinoma, and triple-negative breast cancer [6][7] - The need to enhance the delivery efficiency of ferroptosis inducers to tumor tissues is a critical theme, as several inducers have shown effectiveness in preclinical models but failed to improve patient survival in clinical trials [7][9] Group 2: Nanotechnology and Delivery Systems - Recent advancements in nanotechnology provide new perspectives for the innovation of tumor ferroptosis, particularly through the development of nanodrug delivery systems (NDDS) that can regulate multiple molecular pathways and enhance tumor-specific delivery [4][8] - Multifunctional nanomaterials can serve as nanocarriers for the synergistic delivery of various therapeutic agents, overcoming ferroptosis resistance in cancer cells and effectively targeting multiple molecular pathways [8][9] - NDDS can be designed to respond to tumor-specific stimuli, allowing for spatiotemporal controlled release of ferroptosis inducers, thereby minimizing off-target damage and enhancing therapeutic efficacy [8][9] Group 3: Future Directions - The review establishes a connection between the biology of ferroptosis and nanomaterial science, elucidating how functional nanoplatforms can enhance ferroptosis by modulating dysfunctional organelles and improving the delivery efficiency of inducers [9][27] - The current limitations of ferroptosis in clinical applications and the future development directions based on nanotechnology are summarized, indicating a significant potential for improving clinical outcomes and patient quality of life through enhanced ferroptosis cancer therapies [9][27]

Core Insights - Lung cancer is a leading cause of cancer-related deaths globally, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of cases, and lung adenocarcinoma (LUAD) being the most common subtype. The five-year survival rate for lung adenocarcinoma patients is below 26% [2] - The study published in Cell Discovery reveals that ferroptosis-induced SUMO2 lactylation counteracts ferroptosis by enhancing the degradation of ACSL4 in lung adenocarcinoma, identifying a key regulatory factor in the resistance to ferroptosis and proposing a new strategy for cancer treatment based on ferroptosis [3][8] Group 1: Ferroptosis and Cancer Treatment - Ferroptosis is a regulated form of cell death characterized by the accumulation of reactive oxygen species (ROS), lipid peroxides, and increased levels of divalent iron (Fe2+), showing significant effectiveness in overcoming resistance to traditional cancer therapies [5] - The study indicates that ferroptosis significantly increases lactate accumulation and subsequent protein lactylation, which contributes to the resistance of lung adenocarcinoma cells to ferroptosis [6] Group 2: Key Findings of the Research - SUMO2-K11 lactylation is identified as a critical factor determining the resistance to ferroptosis in lung adenocarcinoma, as it weakens the interaction between SUMO2 and ACSL4, promoting ACSL4 degradation and disrupting lipid metabolism [6][8] - AARS1 is recognized as the lactylation transferase for SUMO2-K11la, while HDAC1 acts as the de-lactylase. The research team developed a cell-penetrating peptide that specifically inhibits SUMO2-K11la, enhancing ferroptosis and increasing the sensitivity of lung adenocarcinoma to the chemotherapy drug cisplatin [6][8]

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].