Therapeutic potential of Cistanche against Parkinson's disease via regulating circulating inflammation: Insights from Mendelian randomization, molecular docking, and in vivo studies.

Parkinson's disease (PD) is the second most common neurodegenerative disorder worldwide, and no curative treatment is currently available. Although inflammation has been increasingly implicated in PD, the causal roles of circulating inflammatory cytokines remain largely unclear, making them potential therapeutic targets. Traditional Chinese Medicine (TCM), characterized by systemic and multi-target regulation, may offer complementary strategies for PD. This study aimed to investigate the therapeutic potential of Cistanche in PD by modulating circulating inflammatory cytokines using an integrated framework combining Mendelian randomization (MR), molecular docking, and in vivo validation. Two-sample MR analysis was empolyed to identify causal associations between circulating inflammatory cytokines and PD. Major active compounds of Cistanche were screened using the TCMSP and ETCM databases. Protein-protein interaction (PPI), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) were performed to characterize cytokine-related functional networks. Molecular docking was employed to evaluate the interactions between the major Cistanche compounds and the key inflammatory targets. Finally, in vivo experiments were conducted for biological validation. MR indicates that CD6, CST5, FGF21, IL-17A, TGF-α, TNFRSF9, CXCL10, CXCL11, IL-5, MMP1, and OPG may be causally associated with PD. Molecular docking revealed that beta-sitosterol, suchilactone, quercetin, and marckine exhibited strong binding affinities with CXCL10, IL-17 A, MMP1, and IL-5, which are closely related to the IL-17 signaling pathway. After 14 days Cistanche treatment, PD model mice exhibited improved motor performance, increased dopaminergic neurons, reduced α-synuclein (α-syn) aggregation, decreased IL-17A/CXCL10/MMP1, and elevated IL-5 levels. Our findings highlight the IL-17-associated circulating inflammatory axis as relevant in PD and support the therapeutic potential of Cistanche through modulation of circulating inflammation.