This research surveyed the therapeutic potential of curcumin (Cur) in Parkinson's disease (PD), focusing on its effects on cuproptosis and underlying molecular mechanisms. A MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced mouse model and a MPP+ (1-methyl-4-phenylpyridinium)-treated PC12 cell model were used in this study. In vivo, Cur treatment significantly mitigated MPTP-treated dyskinesia and lessened the damage of dopaminergic (DA) neurons in SNpc. Additionally, Cur reversed MPTP-induced changes by increasing TH (tyrosine hydroxylase) expression and decreasing α-syn (α-synuclein) accumulation in the SN. In vitro, Cur mitigated MPP+-treated apoptosis and the cytotoxicity of differentiated PC12 cells. Furthermore, Cur reversed MPTP/MPP+-induced changes in the cuproptosis-related protein expression, including DLAT (dihydrolipoamide S-acetyltransferase), FDX1 (ferredoxin 1), and upregulating SLC31A1 (solute carrier family 31 member 1) and HSP70 (heat shock protein 70). 3-MA (3-methyladenine) reversed Cur-mediated expression levels of DLAT, FDX1, SLC31A1, and HSP70 in the PD models. Mechanistically, Cur decreased the expression of p-AKT (p-protein kinase B), p-mTOR (p-mammalian target of rapamycin), and p-P70S6K (p-70 KDa ribosomal protein S6 kinase‌) in the PD models, suggesting it has an inhibitory effect on the AKT/mTOR/P70S6K signaling pathway. Furthermore, pretreatment with SC79 (an AKT activator) reversed Cur-induced autophagy activation, supporting the role of this pathway in Cur-mediated neuroprotection. Cur protected against DA neuronal loss by modulating the interplay between cuproptosis and autophagy via the suppression of the AKT/mTOR/P70S6K. The study findings provide novel insights into the mechanism of Cur's neuroprotective effect, highlighting the AKT/mTOR/autophagy/cuproptosis axis as a potential target and Cur as a medicant for PD management.
