撰文丨王聪 编辑丨王多鱼 排版丨水成文 铁死亡 （Ferroptosis） 是 2012 年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。 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。因此， 铁死亡正在成为是一种极具前景的抗癌新策略。 经典铁死亡通常由诱导剂 （例如 erastin 和 RSL-3） 或 GPX-4 缺失所触发，然而，铁死亡在体内的自然发生无需这些触发因素，其中的机制一直不清楚。 2026 年 2 月 19 日， 哥伦比亚大学 顾伟 教授团队联合匹茨堡大学 Valerian E. Kagan 团队 （顾伟实验室博士后 夏章传 为论文第一作者） ，在国际顶尖学术 期刊 Cell 上发 表了题为： A GPX1-OSBPL8 axis mediates noncanonical in vivo ferroptosis a ...

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 the role of ALDH2*2 mutation in exacerbating acute heart failure post-myocardial infarction by promoting ferroptosis through selective translation of specific mRNAs [4][7]. Group 1: ALDH2 and Its Mutation - ALDH2 plays a crucial role in detoxifying lipid peroxidation products and alcohol metabolism, with the common mutation ALDH2*2 present in 40% of East Asian populations, leading to reduced enzyme activity and increased myocardial infarction risk [3]. - The ALDH2*2 mutation results in decreased ALDH2 protein levels, which disrupts its interaction with the eIF3 complex, promoting the formation of the eIF3E-eIF4G1-mRNA complex that drives the translation of ferroptosis-related genes [6][7]. Group 2: Research Findings - The research involved 177 Chinese patients with acute heart failure, comparing wild-type and ALDH2*2 genotypes, and established a myocardial infarction model in mice [5]. - ALDH2*2 carriers exhibited more severe heart failure post-acute myocardial infarction, characterized by increased bioactive lipids and decreased antioxidants in plasma, indicating ferroptosis [5]. - Inhibition of ferroptosis using Fer-1 significantly improved cardiac function in ALDH2*2 mouse models, reversing markers of ferroptosis [5]. Group 3: Mechanism of Ferroptosis - ALDH2 interacts with the eIF3 complex to prevent the formation of the eIF3E-eIF4G1-mRNA complex, which is disrupted by the ALDH2*2 mutation, leading to increased translation of mRNAs that promote ferroptosis [6]. - Continuous knockdown of eIF3E in myocardial cells can restore cardiac function in ALDH2*2 carriers by alleviating ferroptosis [6][7]. Group 4: Therapeutic Implications - Targeting ferroptosis presents a viable cardiac protection strategy, particularly for ALDH2*2 carriers, to mitigate myocardial injury [5][7].

Investment Rating - The report does not explicitly state an investment rating for the gynecological industry or Polycystic Ovary Syndrome (PCOS) treatments Core Insights - Polycystic Ovary Syndrome (PCOS) is a common endocrine disorder among women of reproductive age, characterized by irregular menstruation, hyperandrogenism, and ovulatory dysfunction, with potential metabolic abnormalities such as obesity and insulin resistance [4][10] - The prevalence of PCOS among reproductive-age women in China ranges from 5% to 10%, influenced by diagnostic criteria and regional factors [4][6] - Current treatment options for PCOS include hormonal therapies, insulin sensitizers, and lifestyle modifications, with a focus on managing symptoms and improving fertility outcomes [15][16] Summary by Sections Clinical Manifestations and Epidemiology - PCOS is associated with symptoms such as irregular menstruation, anovulation, hirsutism, and metabolic issues like obesity and insulin resistance [3][4] - Epidemiological studies indicate varying prevalence rates across different regions in China, with notable figures such as 12.8% in Tianjin among adolescents [6] Impact on Fertility - PCOS is a leading cause of anovulatory infertility, with complications including endometrial hyperplasia and increased miscarriage risk due to hormonal imbalances and metabolic dysfunctions [10][11] - Factors contributing to increased miscarriage rates in PCOS patients include obesity, insulin resistance, and hormonal dysregulation [11] Treatment Options - Key medications for PCOS treatment include progestins, oral contraceptives, insulin sensitizers like Metformin, and ovulation induction agents [15] - The report highlights the importance of insurance coverage for these treatments, with various classifications under the national health insurance system [15] Research Progress - Current research focuses on molecular mechanisms of PCOS, including iron death, circadian rhythms, and genetic factors influencing insulin resistance [16] - There is an emphasis on personalized medicine approaches and the integration of traditional Chinese medicine with modern treatments to enhance patient outcomes [16] Implications for Industry Development - The report suggests that the combined treatment strategies for PCOS can guide pharmaceutical companies in developing targeted therapies that address both reproductive and metabolic health [21]

Investment Rating - The report does not explicitly state an investment rating for the gynecological industry or Polycystic Ovary Syndrome (PCOS) treatment sector Core Insights - Polycystic Ovary Syndrome (PCOS) is a common endocrine disorder among women of reproductive age, characterized by irregular menstruation, hyperandrogenism, and ovulatory dysfunction, with potential metabolic abnormalities such as obesity and insulin resistance [4][10] - The prevalence of PCOS among reproductive-age women in China ranges from 5% to 10%, influenced by diagnostic criteria and regional factors [4][6] - Current treatment options for PCOS include hormonal therapies, insulin sensitizers, and lifestyle interventions, with a focus on managing symptoms and improving fertility outcomes [15][16] Summary by Sections Clinical Manifestations and Epidemiology - PCOS is associated with symptoms such as irregular menstruation, anovulation, hirsutism, and metabolic issues like obesity and insulin resistance [3][4] - Epidemiological studies indicate varying prevalence rates across different regions in China, with rates such as 6.5% in Jinan and 12.8% in Tianjin among adolescents [6] Impact on Fertility - PCOS is a leading cause of anovulatory infertility, with approximately 70% of patients experiencing infertility due to anovulation or oligomenorrhea [11] - Long-term anovulation can lead to endometrial hyperplasia and increased risk of endometrial cancer [11] Treatment Options - Key medications for PCOS treatment include progestins, oral contraceptives, insulin sensitizers like Metformin, and ovulation induction agents [15] - The report highlights the classification of these medications under different insurance categories, indicating their coverage status [15] Research Progress - Current research focuses on molecular mechanisms, personalized medicine, and the integration of traditional Chinese medicine with modern treatments for PCOS [16] - Notable areas of exploration include iron death mechanisms, circadian rhythms, and the role of specific biomarkers in predicting insulin resistance and pregnancy outcomes [16] Implications for Industry Development - The combination of Western and traditional Chinese medicine approaches offers insights for pharmaceutical companies to develop multi-target interventions for PCOS [21] - Understanding the interconnectedness of gynecological diseases can guide companies in creating innovative products that address both reproductive and metabolic health [21]

Core Viewpoint - The study reveals a novel regulatory axis involving GPX4 and ZP3 receptors that impairs antitumor immunity during ferroptosis, suggesting new therapeutic targets for cancer immunotherapy, especially for patients unresponsive to existing treatments [2][3][16]. Group 1: Mechanism of Action - The research identifies that during ferroptosis, cancer cells release GPX4 protein, which binds to ZP3 receptors on dendritic cells, activating a signaling cascade that inhibits glycolysis and impairs dendritic cell maturation and activation, leading to T cell activation defects [3][6][14]. - Disruption of the GPX4-ZP3 interaction can restore dendritic cell metabolic activity and enhance antitumor immunity, indicating a potential therapeutic strategy [3][16]. Group 2: Clinical Implications - Clinical data show that higher serum levels of GPX4 correlate with poorer treatment outcomes, and elevated ZP3 expression is associated with unfavorable prognosis across various solid tumors [16][18]. - In preclinical models, blocking the GPX4-ZP3 interaction significantly enhances the efficacy of chemotherapy, immunotherapy, and radiotherapy, providing a new approach to overcoming tumor resistance [16][19]. Group 3: Future Directions - The findings open avenues for personalized cancer immunotherapy by targeting the GPX4-ZP3 pathway, potentially benefiting patients who do not respond to current immunotherapies [18][19]. - Ongoing research aims to translate these discoveries into clinical applications, with the possibility of using GPX4 and ZP3 levels as biomarkers for tailored treatment strategies [19][20].

Core Viewpoint - Colorectal cancer (CRC) remains a significant health challenge globally, with high incidence and mortality rates, necessitating further research into molecular mechanisms and potential therapeutic targets [1][2]. Group 1: Research Findings - The study published in Signal Transduction and Targeted Therapy indicates that Inhibin beta A (INHBA) drives CRC progression by reprogramming tumor-associated macrophages (TAM) to the M2 phenotype and suppressing mitochondria-dependent ferroptosis in CRC cells [2][7]. - Elevated INHBA expression in CRC tissues correlates with poor clinical outcomes, promoting cancer cell growth, migration, and invasion, while silencing INHBA inhibits these malignant behaviors [5][7]. - Mechanistically, INHBA activates the succinate/SUCNR1 signaling axis by upregulating SLC25A10, promoting M2-like TAM polarization, and inhibits ferroptosis in CRC cells through the mitochondrial glutathione/GPX4 pathway [5][7]. Group 2: Implications for Treatment - The findings provide a theoretical basis for developing INHBA-targeted inhibitors or combined immunotherapy strategies that induce ferroptosis, potentially improving CRC treatment outcomes [2][7].

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, and represents a promising new strategy for cancer treatment by inducing lipid peroxidation [1][6]. Group 1: Research Findings - The study published in Molecular Cell highlights that PRDX6 is a key regulatory factor of GPX4, which helps resist ferroptosis, and targeting PRDX6 can enhance the anti-tumor effects mediated by ferroptosis [2][6]. - The research team identified that PRDX6 influences the localization and function of GPX4, thereby contributing to the resistance against ferroptosis [3][6]. - PRDX6 has phospholipase A2 activity, catalyzing the conversion of peroxidized phospholipids into lysolipids and oxidized fatty acids, which is crucial for its interaction with GPX4 [4][6]. Group 2: Implications for Cancer Treatment - Combining PRDX6 inhibition with ferroptosis inducers can increase lipid peroxidation and effectively suppress tumor growth in mouse models of liver and ovarian cancer, including patient-derived models [4][6]. - High expression of PRDX6 is associated with shorter progression-free survival in various human cancer types, indicating its potential as a therapeutic target [4][6].

Core Viewpoint - Triple-negative breast cancer (TNBC) is characterized by high invasiveness and poor prognosis due to the lack of specific treatment targets and high rates of postoperative recurrence and metastasis. Current treatments primarily involve surgical resection followed by chemotherapy, but inherent chemotherapy resistance necessitates new effective treatment strategies. The study introduces a promising approach using nanozyme-based therapy for postoperative adjuvant treatment of TNBC [1][4][7]. Group 1: Research Background - TNBC is the most aggressive subtype of breast cancer, with high recurrence and mortality rates. It lacks expression of estrogen receptors, progesterone receptors, and HER2, leading to a lack of precise treatment targets. The main treatment methods are surgical resection and postoperative chemotherapy, but challenges such as residual metastatic lesions and chemotherapy resistance contribute to high recurrence and metastasis rates [4][5]. - Recent studies indicate that immune checkpoint blockade (ICB) therapy shows potential in TNBC treatment due to the high density of tumor-infiltrating lymphocytes. However, resistance to immune checkpoint inhibitors and low immune response limit treatment efficacy, highlighting the need for enhanced antitumor immunity [4][5]. Group 2: Study Findings - The research combines iron-based unit point nanozymes (MFCA) with a responsive hydrogel delivery system to address two key challenges in TNBC treatment: eliminating residual tumor satellite lesions and inhibiting postoperative metastasis. This hydrogel composite can be directly injected into the surgical cavity for sustained release of MFCA, inducing ferroptosis in TNBC cells and enhancing immunogenicity [2][6]. - The study developed a biodegradable unit point nanozyme-loaded hydrogel that effectively inhibits postoperative metastasis and systemic recurrence in TNBC, providing a direct, efficient, and safe adjuvant treatment method to improve patient prognosis [7].

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].