Targeting ferroptosis and cuproptosis in gastrointestinal cancers: molecular mechanisms, metabolic vulnerabilities, and therapeutic interventions

作者：Yang Zhang, Yixiang Gu, Ming Zhan, Linhua Yang, Hui Wang · 发表于：Molecular Biomedicine · 年份：2025 · DOI：10.1186/s43556-025-00347-7 · 被引用次数：12 · 研究领域：Ferroptosis and cancer prognosis、Cancer, Lipids, and Metabolism、Clusterin in disease pathology

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 ...