Ischemic stroke (IS), a leading cause of disability and mortality worldwide, results from cerebral vascular occlusion and is associated with profound energy metabolism disorders, including oxidative phosphorylation, glycolysis, and fatty acid metabolism. Herba Siegesbeckiae (HS), a traditional Chinese medicinal herb, has shown neuroprotective potential by modulating metabolic and inflammatory pathways, but its mechanisms in IS remain unclear.

Active compounds of HS were identified from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform. Potential targets were predicted using GeneCards, DisGeNET, and SwissTargetPrediction and filtered for genes related to energy metabolism in IS. A protein-protein interaction network was constructed using STRING and analyzed with Cytoscape 3.9.1 Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed with the clusterProfiler package in R, and molecular docking with AutoDock Vina evaluated compounds-target affinities.

Nine active compounds and 252 potential target genes were identified. Among 21 core targets, IL6, CYP3A4, and PPARG showed the highest network centrality. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses indicated enrichment in inflammatory regulation, lipid metabolism, and oxidative stress-related pathways. Molecular docking showed strong binding affinities, with hederagenin demonstrating the most stable interaction with CYP3A4.

HS may regulate energy metabolism in IS through multi-target, multi-pathway mechanisms, exerting neuroprotective effects via anti-inflammatory and metabolic regulation.