基于多组学孟德尔随机化和生物信息学方法探讨雷丸治疗癫痫内在机制OA

Epilepsy is a complex chronic neurological disorder,existing antiepileptic drug face limitations such as treatment resistance.Omphalia lapidescens sclerotium(lei wan,omphalia),a traditional fungal medicine,has demonstrated certain anticonvulsant effects,but its mechanisms remain unclear.This study aims at systematically elucidating the mechanism of omphalia in treating epilepsy through integrating network pharmacology,multi-omics Mendelian randomization(MR),and various bioinformatic approaches.Active ingredients of omphalia were screened using the TCMSP database,and their potential therapeutic targets were predicted.By combining MR analysis based on eQTL/pQTL data,differential gene expression analysis from microarray datasets and machine learning models,key targets for omphalia in epilepsy treatment were identified,and core targets were selected through topological analysis.Subsequently,GO/KEGG enrichment analysis,gene set enrichment analysis,immune infiltration assessment,molecular docking,and gut microbiota MR were applied to explore the functional mechanisms of omphalia.Three active ingredients,sitosterol,stigmasterol,and ergosterol peroxide,along with 87 potential targets were identified.Intersection with epilepsy-related targets obtained through various methods yielded seven key targets:RORC,S1PR3,ADORA1,PTGS2,RORA,CDC25B,and TBXAS1,among which PTGS2 and RORA were identified as core targets.Molecular docking showed binding energies below-11.0 kcal/mol for all active ingredients with core targets,indicating strong binding affinity.Enrichment analysis revealed that these targets are primarily involved in regulating lipid metabolism,circadian rhythm,inflammatory response,and sphingolipid signaling pathways.Immune infiltration analysis suggests that RORA activates CD8+T cells and inhibits pro-inflammatory cells,while PTGS2 regulates dendritic cell activation.MR analysis of gut microbiota indicated causal associations between PTGS2/RORA and 17 microbial taxa including Bifidobacterium,suggesting omphalia might exert antiepileptic effects by modulating the gut-brain axis.This study reveals that omphalia exerts anticonvulsant effects through multi-target and multi-pathway synergistic regulation of immune inflammation,lipid metabolic homeostasis,circadian rhythm,and gut-brain interaction.The research overcomes the limitations of traditional network pharmacology and provides a reference for the clinical translation of omphalia and optimization of epilepsy treatment strategies.