This study investigated the protective effect of licochalcone A (LCA) on PC12 cells damaged by the neurotoxin 6-hydroxy-dopamine (6-OHDA),elucidated its mechanism through molecular simulation.At first,the study determined the scavenging activity of LCA on ABTS and DPPH free radicals in vitro.Secondly,the experiment measured the content of lactate dehydrogenase (LDH) in cell medium and employed the MTT assay to evaluate the protective efficacy of LCA against 6-OHDA-induced damage in PC12 cells. 2′,7′-Dichlorodihydrofluorescein diacetate (DCFH-DA) staining was used to determine the effect of LCA on reactive oxygen species in PC12 cells injured by 6-OHDA.The contents of total glutathione (GSH),superoxide dismutase (SOD) and total antioxidant capacity (T-AOC) in each group were detected to evaluate the endogenous antioxidant capacity.The effect of LCA on the expression of nuclear factor erythroid-2 related factor 2（Nrf2） protein was analyzed by Western blot.Finally,molecular docking and simulation methods were utilized to study the binding site and ability of LCA on Keap1 protein,and calculate and analysis its absorption,distribution,metabolism,excretion,toxicity (ADMET).The results indicated that LCA possesses significant free radical scavenging activity in vitro.Treatment with LCA markedly enhanced PC12 cell viability under 6-OHDA stress,diminished reactive oxygen species production,and elevated GSH,SOD,and T-AOC levels under these conditions.Furthermore,Western blot analysis revealed that LCA treatment increased the expression of Nrf2 protein.Molecular docking and dynamic simulations confirmed stable covalent bonding between LCA and Keap1 proteins,ADMET prediction suggesting that LCA could be a promising therapeutic agent.These observations suggest that LCA confers protection to PC12 cells damaged by 6-OHDA by modulating endogenous antioxidant responses within biological systems.