Network pharmacology-guided systems biology reveals β-Sitosterol’s multi-target role in reversing 7-ketocholesterol-induced oxidative and inflammatory stress

7-Ketocholesterol (7-KC), a cytotoxic oxysterol generated through cholesterol oxidation, plays a central role in the progression of atherosclerosis, neurodegeneration, and metabolic syndromes through mitochondrial dysfunction, ROS overproduction, and NLRP3 inflammasome activation. This study presents the first integrative systems pharmacology analysis exploring the molecular mechanisms by which β-sitosterol (BS), a phytosterol with antioxidant and anti-inflammatory properties, mitigates 7KC-induced toxicity. Shared targets between BS and 7KC were identified through target prediction databases and subjected to protein–protein interaction (PPI) network analysis using Cytoscape with bottleneck centrality. Top hub genes were functionally enriched using Gene Ontology and KEGG pathway tools, revealing BS’s modulation of nuclear receptor activity, redox homeostasis, and OXPHOS pathways. BS targets were localized across cytosol, nucleus, and membrane compartments, supporting its multi-compartmental regulatory role. This mechanistic framework highlights BS as a potential nutraceutical intervention for 7KC-driven chronic diseases, including atherosclerosis, NAFLD, and Alzheimer’s disease, warranting further biological validation.