Prediction of potential natural compounds for Parkinson's disease treatment:Dual insights from gut microbes to ferroptosis

CHEN Junlei; DING Tunan; KONG Weitai; WANG Weihao; ZHANG Zhenguo; LI Jiayi; ZHAO Yuyuan; LI Zhangkai; ZHENG Hongbo; GUO Yuanyuan; FU Qiang; FU Yin

doi:10.13506/j.cnki.jpr.2025.09.001

Abstract：Objective To explore the causal association between Parkinson's disease(PD)and intestinal microbiota(IF)through Mendelian randomization(MR),predict potential Chinese herbal medicines and components that treat PD by regulating IF,and analyzing its mechanism of action from the perspective of ferroptosis.Methods Two sample MR analysis was carried out based on genome-wide association study data from Mibiogen and IEU databases.g:Snpense and Coremine databases were used to locate single nucleotide polymorphism(SNP)neighboring genes and predict Chinese herbal medicine,and the classification of Chinese herbal medicine was standardized in combination with pharmacopoeia and textbooks.Single cell subpopulation expression analysis was performed on the predicted targets.Based on the GEO dataset,the expression differences of PD and ferroptosis genes were compared,and the hub genes were screened by weighted gene coexpression network analysis(WGCNA).The active ingredient targets of Chinese herbal medicine were collected from TCMSP and Herb databases,and DrugnomeAI was used to predict the druggability and perform molecular docking validation.Results MR analysis found that Candidatus Soleaferrea(OR,1.192;95％CI:1.041～1.366,P=0.011),Clostridium sensu strictol(OR,1.356;95％CI:1.089～1.690,P=0.007)are risk factors of PD.The primary therapeutic Chinese herbal medicines involved cooling and neutral properties,Sweet,bitter and pungent flavours,primarily targeting the heart,liver,and spleen meridians,and were mostly categorized as heat-clearing and detoxifying,Albizziajulibrissin,Forsythia suspensa and Smilax are highly correlated.Single cell analysis showed that there were differences in the expression of drug targets in cell subsets.Ferroptosis related gene FDFT1 is significantly expressed in PD.223 hub genes were screened by WGCNA,and 18 of them intersected with drug targets.11 targets such as CYP2A6 and MAP2K2 have good druggability.Molecular docking showed that bicuculline-TOP 1 binds best.Conclusion The association between IF and ferroptosis related gene expression provides a dual perspective for exploring new strategies for PD treatment,and provides a new idea for the innovation of PD treatment strategies.