Regulated Metal-Dependent Cell Death: Mechanistic Intersections of Ferroptosis and Cuproptosis in Human Disease and Toxicology

Abstract

Ferroptosis and cuproptosis are metal-dependent forms of regulated cell death that are increasingly recognised as important mechanisms linking metal homeostasis, mitochondrial metabolism, oxidative stress, and disease pathogenesis. Ferroptosis is primarily driven by iron-dependent lipid peroxidation following disruption of antioxidant defences such as the glutathione-GPX4 axis, whereas cuproptosis is associated with intracellular copper accumulation, copper binding to lipoylated mitochondrial proteins, protein aggregation, iron-sulfur cluster destabilisation, and impairment of tricarboxylic acid cycle function. This review summarises the molecular basis of ferroptosis and cuproptosis and discusses their mechanistic intersections in human disease and toxicology. Particular emphasis is placed on the toxicological relevance of metal-dependent cell death pathways in environmental exposure, metal toxicity, xenobiotic-induced injury, and organ-specific toxicological responses. Literature was searched using PubMed, Scopus, Web of Science, and Google Scholar for English-language studies published up to February 2026. The review highlights shared regulatory nodes, including mitochondrial dysfunction, reactive oxygen species generation, metal transport systems, glutathione metabolism, autophagy, mitophagy, and transcriptional regulators such as Nrf2, p53, and HIF-1α. Evidence linking these pathways to cancer, neurodegenerative disorders, metabolic diseases, and inflammatory or infectious conditions is discussed, with emphasis on the biological contexts in which metal-dependent cell death may contribute to tissue injury or therapeutic vulnerability. Pharmacological approaches, including iron and copper chelation, ionophore-based modulation, ferroptosis inhibitors, and emerging dual-pathway strategies, are reviewed with attention to their current limitations. The proposed framework of metalloptosis is presented as an integrative concept for understanding metal-regulated cell death, while acknowledging the need for stronger biomarkers, validated models, and careful translational evaluation