Artesunate alleviates Parkinson's disease by targeting astrocyte MT2A to attenuate dopamine neuronal cuproptosis

Parkinson's disease (PD) is the second most common prevalent neurodegenerative disease. Recent studies revealed that dysregulation of copper homeostasis was associated with the progression of PD. However, safe and efficient therapeutic drugs were deficient. Our study first demonstrated that Artesunate (AS) targeted on astrocyte to attenuate 6-OHDA-induced dopamine (DA) neurotoxicity. Furtherly, using HuProt™ 20 K human proteome microarray and SPR analysis, it was demonstrated and validated that metallothionein 2 A (MT2A) was a direct AS-binding protein, which high-expressed in astrocyte and up-regulated by AS. In addition, AS decreased intracellular Cu²⁺ level and regulated the expression of cuproptosis-associated proteins, such as FDX1, CTR1 and Lip-DLAT. Finally, rescue experiments indicated that AS-mediated DA neuroprotection, Cu²⁺ reduction and anti-cuproptosis effects were eliminated by MT2A knockdown and MT2A-Lys-31 was a key functional site. Taken together, AS provided neuroprotection against PD via up-regulation of astrocyte MT2A expression, which further decreased intracellular Cu²⁺ level and improved DA neuronal cuproptosis. These findings provide a valuable resource for AS-binding proteins and present a potential application of AS on PD treatment.