Cuproptosis in Cancer: A Novel Metal-induced Cell Death Pathway

Cuproptosis is a recently identified form of copper-dependent regulated cell death that functions through a mitochondrial mechanism distinct from apoptosis, ferroptosis, and other canonical pathways.It is triggered when excess intracellular copper binds to lipoylated enzymes of the tricarboxylic acid (TCA) cycle, causing proteotoxic stress, collapse of iron-sulfur (Fe-S) cluster function, and mitochondrial failure.This narrative review synthesizes emerging evidence on the mechanistic basis of cuproptosis, key molecular regulators such as ferredoxin 1 (FDX1), and the increasing interest in utilizing this pathway for cancer therapy.Preclinical studies indicate that copper ionophores, copper chelators, and nanoparticle-based delivery systems can modulate cuproptosis to overcome drug resistance in several tumor types, although clinical results remain varied.Challenges include metabolic heterogeneity within the tumor, resistance mechanisms like adenosine triphosphate (ATP)/B-mediated copper export, and an incomplete understanding of downstream signaling.Despite these uncertainties, cuproptosis presents a promising therapeutic approach for cancers that depend heavily on mitochondrial metabolism.Ongoing mechanistic and translational research will be crucial for refining biomarkers, identifying effective drug combinations, and determining optimal contexts for cuproptosis-targeted treatments in oncology.