Cuproptosis: Current insights into its multifaceted role in disease, cancer, and translational/therapeutic opportunities
Diego Liviu Boaru, Diego De León-Oliva, Patricia De Castro-Martinez, Cielo García‐Montero, Oscar Fraile‐Μartinez, Beatriz García-González, Isabel Pérez-González, Majd N Michael Alhaddadin, Silvestra Barrena-Blázquez, Laura López-González, Basilio de la Torre, Luis G. Guijarro, Leonel Pekarek, Miguel A. Sáez, Laura Ríos-Espinosa, Maria J. Garrido-Gil, M.J. Gimeno, Tatiana Pekarek, Raúl Dı́az, Melchor Alvarez-Mon, Miguel Á. Ortega
Abstract
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.