Cuproptosis

Cuproptosis is a form of regulated cell death driven by intracellular copper accumulation acting on the mitochondria. Its defining mechanism is unusual among cell-death pathways in that it has no dedicated executioner protein: copper binds directly to the lipoyl moieties of tricarboxylic acid (TCA) cycle enzymes, most critically dihydrolipoamide S-acetyltransferase (DLAT), causing them to aggregate. The aggregated, lipoylated proteins are themselves the toxic species, and their accumulation coincides with destabilization of iron–sulfur cluster proteins, blocking pyruvate entry into the TCA cycle and producing a proteotoxic mitochondrial crisis that kills the cell. Ferredoxin 1 (FDX1) is required at two points — reducing Cu²⁺ to the more reactive Cu⁺ and supporting protein lipoylation — which makes it the principal determinant of susceptibility, alongside the copper transporters SLC31A1 (CTR1) for import and ATP7A for efflux.

Because the death depends on lipoylated TCA enzymes being present and active, it selectively kills cells that respire: tumors relying on oxidative phosphorylation are sensitive, while glycolytic cells largely resist, and the same lesion can be induced experimentally with copper ionophores such as elesclomol that carry copper past normal import controls. This metabolic dependency is what distinguishes cuproptosis mechanistically from ferroptosis, apoptosis and pyroptosis, and what makes it attractive as a way to attack tumors selected by metabolic state rather than by mutation, potentially circumventing conventional resistance.

Its significance extends beyond oncology. copper overload injures neurons and underlies Wilson disease, in which failure of hepatic copper export produces liver and neurological damage, and cuproptosis has been implicated in subarachnoid hemorrhage, preeclampsia and fibroblast-driven fibrotic disease including endometriosis. Its capacity to elicit immunogenic cell death — releasing damage-associated molecular patterns that stimulate dendritic cells, macrophages and CD8+ T cells — places it at the intersection of metabolic disruption and antitumor immunity, and is the rationale for combining copper-directed agents with immunotherapy.