Cuproptosis Inhibition by C-Phycocyanin Confers Neuroprotection against Copper-Induced Mitochondrial Damage and Cognitive Impairment.

Copper (Cu) is an essential trace element, but its dyshomeostasis has been increasingly linked to neurotoxicity and neurodegenerative diseases. The specific contribution of cuproptosis, a novel copper-dependent regulated cell death pathway, to neuronal damage remains poorly defined. This study evaluated the neuroprotective potential of C-phycocyanin (C-PC), a natural compound derived from Spirulina, against Cu-induced neurotoxicity, with a focus on cuproptosis. In vitro, C-PC treatment markedly attenuated Cu-induced cell death in mouse neuronal cells. It restored mitochondrial membrane potential, ameliorated oxidative stress by reducing malondialdehyde (MDA) and elevating adenosine triphosphate (ATP) levels, and restored key cuproptosis markers, including FDX1 and lipoylated DLAT. In Cu-exposed mice, oral administration of C-PC ameliorated cognitive deficits, as assessed by the Morris water maze test, and reduced neuronal loss in the hippocampus. Biochemical analysis of brain tissue further confirmed that C-PC mitigated oxidative damage and suppressed the expression of cuproptosis-related proteins. These results indicate that C-PC is a potent inhibitor of cuproptosis, exerting its effects primarily by preserving mitochondrial integrity and reducing proteotoxic stress. Given its biocompatibility and natural origin, C-PC represents a promising therapeutic candidate for countering Cu-induced neurotoxicity.