Citrus Peel Xanthophylls Orchestrate Lipid-Glucose-Inflammation Axis Reprogramming in Cardiometabolic Syndrome: Integrative In Silico and In Vivo Evidence.

Cardiometabolic syndrome (CMS) involves interconnected dysregulation of lipid, glucose, and inflammatory pathways. Citrus peel, an agro-industrial byproduct, is rich in xanthophylls with potential multitarget effects, yet their integrated mechanisms remain unclear. This study aimed to investigate the mechanistic basis and therapeutic efficacy of a citrus peel xanthophyll fraction (CPXF) in modulating the lipid-glucose-inflammation axis through integrated in silico and in vivo approaches. CPXF was characterized via UHPLC-HRMS/MS. Network pharmacology and molecular docking identified target interactions. In vivo validation was conducted in high-fat diet plus fructose-induced CMS rats, evaluating metabolic, inflammatory, oxidative, and gene expression parameters. β-cryptoxanthin, violaxanthin, and lutein were dominant compounds. Key targets included PPARG, AMPK, SREBP1, and MMP9, with strong binding affinities (ΔG up to -10.3 kcal/mol). CPXF significantly improved glucose homeostasis, insulin resistance, lipid profile, and OGTT outcomes. It reduced TNF-α, IL-6, and CRP, attenuated oxidative stress (↓MDA; ↑SOD, CAT, GSH), and restored hepatic function. Gene expression analysis showed upregulation of Ampk and Pparg and suppression of Srebp1c. CPXF exerts synergistic, multitarget effects across the lipid-glucose-inflammation axis via AMPK activation, PPAR-γ modulation, and SREBP-1c suppression, supporting its potential as a food-derived strategy for CMS management.