Boaru Diego Liviu, Leon-Oliva Diego De, Castro-Martinez Patricia De, Garcia-Montero Cielo, Fraile-Martinez Oscar, García-González Beatriz, Pérez-González Isabel, Michael Alhaddadin Majd N, Barrena-Blázquez Silvestra, Lopez-Gonzalez Laura, la Torre Basilio de, Guijarro Luis G, Pekarek Leonel, Saez Miguel A, Ríos-Espinosa Laura, Garrido-Gil María Jesús, Gimeno-Longas Maria José, Pekarek Tatiana, Diaz-Pedrero Raul, Alvarez-Mon Melchor, Ortega Miguel A
Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, Network Biomedical Research Center for Liver and Digestive Diseases (CIBEREHD), University of Alcalá, Alcala de Henares 28801, Spain; Ramón y Cajal Institute of Sanitary Research (IRYCIS), Madrid 28034, Spain.
Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, Network Biomedical Research Center for Liver and Digestive Diseases (CIBEREHD), University of Alcalá, Alcala de Henares 28801, Spain.
Biomed Pharmacother. 2025 Aug 6;190:118422. doi: 10.1016/j.biopha.2025.118422.
Copper is a vital trace element involved in numerous physiological processes, including mitochondrial respiration, antioxidant defense, and enzymatic function. Its homeostasis is tightly regulated through complex transport systems to avoid both deficiency and toxicity. Recent research has unveiled cuproptosis, a unique form of regulated cell death triggered by copper accumulation in mitochondria, and cuproplasia, a copper-induced mechanism that promotes cell proliferation and tumor progression. This review highlights the dual role of copper in health and disease, emphasizing its pathological implications across multiple systems, including cardiovascular, neurological, hepatic, and musculoskeletal conditions. Importantly, a major focus of this review is the role of copper in cancer. Elevated copper levels are commonly observed in tumor tissues and circulation, supporting oncogenic pathways such as PI3K/AKT, MAPK, HIF-1α, and Wnt/β-catenin. Copper enhances tumor cell proliferation, angiogenesis, and metastasis, while also contributing to chemotherapy resistance. Conversely, cuproptosis offers a novel vulnerability in tumors with high mitochondrial activity, where copper accumulation induces cell death via aggregation of lipoylated TCA enzymes and proteotoxic stress. This duality positions copper both as a driver of malignancy and a therapeutic agent. Copper-based therapies, including ionophores, chelators, and copper-dependent nanoparticles, are emerging as promising tools to selectively induce cancer cell death or modulate the tumor microenvironment. Cuproptosis-related genes (CRGs) and long non-coding RNAs (lncRNAs) may serve as predictive biomarkers for prognosis and treatment response. Future research will be essential to fully harness copper´s diagnostic and therapeutic potential in cancer.
铜是一种重要的微量元素，参与众多生理过程，包括线粒体呼吸、抗氧化防御和酶功能。其体内平衡通过复杂的转运系统进行严格调控，以避免缺乏和中毒。最近的研究揭示了铜死亡，这是一种由线粒体中铜积累引发的独特的程序性细胞死亡形式，以及铜增生，这是一种铜诱导的促进细胞增殖和肿瘤进展的机制。本综述强调了铜在健康和疾病中的双重作用，重点阐述了其在多个系统中的病理影响，包括心血管、神经、肝脏和肌肉骨骼疾病。重要的是，本综述的一个主要重点是铜在癌症中的作用。肿瘤组织和循环中通常观察到铜水平升高，支持PI3K/AKT、MAPK、HIF-1α和Wnt/β-连环蛋白等致癌途径。铜增强肿瘤细胞增殖、血管生成和转移，同时也导致化疗耐药。相反，铜死亡在具有高线粒体活性的肿瘤中提供了一种新的脆弱性，其中铜积累通过脂酰化三羧酸循环酶的聚集和蛋白毒性应激诱导细胞死亡。这种双重性使铜既是恶性肿瘤的驱动因素，又是一种治疗剂。基于铜的疗法，包括离子载体、螯合剂和铜依赖性纳米颗粒，正成为选择性诱导癌细胞死亡或调节肿瘤微环境的有前途的工具。铜死亡相关基因（CRG）和长链非编码RNA（lncRNA）可能作为预后和治疗反应的预测生物标志物。未来的研究对于充分利用铜在癌症中的诊断和治疗潜力至关重要。
