Zhang Yang, Gu Yixiang, Zhan Ming, Yang Linhua, Wang Hui
Department of Biliary-Pancreatic Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.
Shanghai Key Laboratory of Biliary Tract Disease, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.
Mol Biomed. 2025 Nov 7;6(1):101. doi: 10.1186/s43556-025-00347-7.
Gastrointestinal (GI) malignancies represent a significant global health burden, characterized by high mortality rates and profound resistance to conventional therapies. This necessitates the exploration of novel therapeutic vulnerabilities, and two recently discovered forms of regulated cell death, ferroptosis and cuproptosis, offer promising metabolism-centered strategies. Ferroptosis is a non-apoptotic pathway driven by iron-dependent lipid peroxidation, canonically suppressed by the glutathione peroxidase 4 (GPX4) axis. In contrast, cuproptosis is a distinct process wherein excess copper induces lethal proteotoxic stress through direct binding to lipoylated components of the tricarboxylic acid (TCA) cycle. Critically, these pathways are not mutually exclusive; instead, they are intricately connected through shared molecular nodes and metabolic dependencies, including redox homeostasis, key signaling proteins, and mitochondrial integrity. This review systematically examines the molecular crosstalk between ferroptosis and cuproptosis, highlighting the synergistic potential of their co-activation as a powerful anti-cancer strategy in GI tumors. We systematically evaluate both preclinical evidence and clinical studies for therapeutic interventions, ranging from small-molecule inducers to advanced nanoplatforms and immunotherapy combinations. Furthermore, we discuss the pressing challenges of identifying predictive biomarkers for patient stratification and overcoming adaptive resistance. Ultimately, deciphering the ferroptosis-cuproptosis nexus holds immense potential to unlock a new paradigm of synergistic therapies, paving the way for more effective clinical management of GI malignancies.
胃肠道（GI）恶性肿瘤是一项重大的全球健康负担，其特征是死亡率高且对传统疗法具有高度抗性。这就需要探索新的治疗弱点，最近发现的两种程序性细胞死亡形式——铁死亡和铜死亡，提供了有前景的以代谢为中心的策略。铁死亡是一种由铁依赖性脂质过氧化驱动的非凋亡途径，通常由谷胱甘肽过氧化物酶4（GPX4）轴抑制。相比之下，铜死亡是一个独特的过程，其中过量的铜通过直接与三羧酸（TCA）循环的脂酰化成分结合，诱导致命的蛋白毒性应激。至关重要的是，这些途径并非相互排斥；相反，它们通过共同的分子节点和代谢依赖性错综复杂地联系在一起，包括氧化还原稳态、关键信号蛋白和线粒体完整性。本综述系统地研究了铁死亡和铜死亡之间的分子串扰，强调了它们共同激活作为胃肠道肿瘤强大抗癌策略的协同潜力。我们系统地评估了从小分子诱导剂到先进纳米平台和免疫治疗组合等治疗干预措施的临床前证据和临床研究。此外，我们讨论了识别预测生物标志物以进行患者分层和克服适应性耐药性的紧迫挑战。最终，解读铁死亡 - 铜死亡关系具有巨大潜力，可开启协同治疗的新范式，为胃肠道恶性肿瘤更有效的临床管理铺平道路。
