Integrative Network Analysis of Antioxidant Nutrients Targeting 7-Ketocholesterol-Induced Lipotoxicity via Sterol Metabolism and Organelle Protection Pathways

Abstract

7-Ketocholesterol (7-KC), a cytotoxic oxysterol, contributes to atherosclerosis, neurodegeneration, and metabolic disorders by promoting oxidative stress, inflammation, and dysfunction of organelles including mitochondria, peroxisomes, lysosomes, and the endoplasmic reticulum, ultimately leading to cell death. Nutritional biomedicine offers potential strategies to counteract these effects using antioxidant nutrients and probiotics. In this study, genes associated with 7-KC toxicity were retrieved from GeneCards, and targets of quercetin, luteolin, butyrate, Docosahexaenoic Acid (DHA), and vitamin E were predicted using SwissTargetPrediction. Overlapping targets were identified via an interactive Venn tool and analyzed through STRING protein–protein interaction networks, CytoHubba hub ranking, and Gene Ontology (GO)/ClueGO pathway enrichment. Twenty shared genes were identified, with Peroxisome Proliferator-Activated Receptor Gamma (PPARG), AKT Serine/Threonine Kinase 1 (AKT1), Amyloid Precursor Protein (APP), and Matrix Metalloproteinase-9 (MMP9) as key hubs. Enriched processes included sterol metabolism, cholesterol efflux, inflammatory regulation, and organelle protection, indicating multi-target modulation. These findings support that combinatorial nutrient interventions can restore sterol homeostasis, mitigate oxidative stress, and attenuate 7-KC-induced pathologies.