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In a rotenone-induced Parkinson's disease (PD) rat model, behavioral investigation, pathological examination, inflammatory factor analysis, and mitochondrial structure and function investigation verified the anti-PD efficacy of nardosinone. A combined transcriptome and proteome analysis proposed that the anti-PD target of nardosinone is the slc38a2 gene and may involve the GABAergic synaptic pathway and cAMP-signaling pathway. Analysis of targeted slc38a2 knockout cells and expression of key enzyme-encoding genes in both pathways verified the target and pathways proposed by the 'omics analysis. This further confirms that nardosinone can regulate the slc38a2 gene, a potential new target for the treatment of Parkinson's disease, and plays an anti-PD role through the GABAergic synaptic and cAMP pathways. [Display omitted] • Nardosinone improves rotenone-induced motor and cognitive impairment in rats. • Nardosinone can alleviate rotenone-induced pathological manifestations in rats. • Nardosinone anti-PD by regulating the GABAergic synaptic and cAMP pathways. [ABSTRACT FROM AUTHOR]