OBJECTIVE: p53 plays a critical role in Parkinson's disease (PD) pathogenesis. p53 activation induces mitochondrial dysfunction and reactive oxygen species (ROS) production, contributing to progressive dopaminergic neuron degeneration. Although α-lipoic acid (ALA) exhibits neuroprotective effects in neurodegeneration, its underlying mechanisms remain unclear. This study investigated the neuroprotective role and molecular mechanism of ALA in 1-methyl-4-phenylpyridinium (MPP+)- treated PC12 cells, a cellular model of dopaminergic toxicity. METHODS: Neuroprotective effects of ALA on dopaminergic neurons were assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay for cell viability, Hoechst 33258 staining and flow cytometry to detect cellular apoptosis, and western blot analysis. RESULTS: ALA treatment significantly inhibited p53 expression and attenuated MPP+-induced apoptosis in dopaminergic neurons. ALA also prevented annexin A2 degradation and protected PC12 cells from MPP+-induced toxicity. CONCLUSIONS: ALA downregulates p53 expression by preventing annexin A2 degradation, thereby reducing p53 protein levels and providing neuroprotection under neurodegenerative conditions. This suggests the potential of ALA in modulating p53 pathways for PD therapy.