From Metal Stress to Regulated Cell Death: An Evidence Framework for Ferroptosis–Cuproptosis Crosstalk in Cancer

作者：Andrada-Adelaida Belbe, Lorin-Manuel Pîrlog, Andrei Sporiș, Adela Pitforodeschi, Alissia-Nicoleta Pilatec, R. Băilă, I. Rusu, M. Dobrescu, M. Militaru, I. Iordănescu, A. Catană · 发表于：Cells · 年份：2026 · DOI：10.3390/cells15151421 · 研究领域：Medicine

Highlights What are the main findings? Ferroptosis and cuproptosis are distinct but connected metal-dependent forms of regulated cell death that expose cancer-specific metabolic liabilities. The manuscript separates validated pathway regulators from correlative genes, lncRNAs, prognostic signatures, and generic oxidative injury markers. What are the implications of the main findings? Mechanism-guided translation requires integrated biomarkers of metal handling, lipid remodelling, antioxidant reserve, mitochondrial metabolism, and protein lipoylation. Therapeutic strategies should prove pathway engagement with pharmacodynamic endpoints rather than relying on ROS accumulation or reduced viability alone. Abstract Resistance to apoptosis, metabolic plasticity, and redox adaptation are major contributors to cancer progression and treatment failure. Ferroptosis and cuproptosis have therefore emerged as metal-dependent forms of regulated cell-death programs with potential relevance for tumours that survive conventional therapy. Ferroptosis is driven by iron-dependent phospholipid peroxidation when glutathione peroxidase 4 (GPX4)-dependent and parallel antioxidant systems fail, whereas cuproptosis depends on mitochondrial copper engagement of lipoylated tricarboxylic-acid-cycle proteins, lipoylated-protein aggregation, iron–sulfur protein destabilization, and proteotoxic stress. This review integrates the molecular basis, genetic architecture, long non-coding RNA (lncRNA)-mediated re...