Abstract
HIV/AIDS remains a major global health challenge, with immune dysfunction, chronic inflammation, and comorbidities sustained by latent viral reservoirs that evade antiretroviral therapy. Euclea natalensis, a medicinal plant widely used in Southern African ethnomedicine, remains underexplored for its potential against HIV. An integrative systems pharmacology and molecular modeling framework was employed, including ADME profiling, target mapping, PPI network analysis, GO and KEGG pathway enrichment, BA-TAR-PATH analysis, molecular docking, MD simulations, and MM/GBSA calculations, to investigate the mechanistic roles of E. natalensis phytochemicals in HIV pathogenesis. Sixteen phytochemicals passed ADME screening and mapped to 313 intersecting host targets, yielding top ten hub genes with GO annotations in immune-metabolic, apoptotic, and nuclear signaling pathways. KEGG analysis revealed the enrichment of HIV-relevant pathways, including Th17 cell differentiation (hsa04659), PD-L1/PD-1 checkpoint (hsa05235), IL-17 signaling (hsa04657), HIF-1 signaling pathway (hsa04066), and PI3K-Akt (hsa04151). Lead phytochemicals, diospyrin and galpinone, strongly targeted key hub proteins (NFκβ1, STAT3, MTOR, HSP90AA1, and HSP90AB1), demonstrating favorable binding affinities, conformational stability, and binding free energetics compared to reference inhibitors. E. natalensis phytochemicals may modulate Th17 differentiation, HIV latency circuits, and comorbidity-linked signaling by targeting multiple host pathways, supporting their potential as multi-target therapeutic candidates for adjunct HIV/AIDS treatment and immunotherapy.