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

ABSTRACT

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 (Δ G 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.