Research Advances on the Molecular Structural Basis and Mechanisms of Quercetin and Its Derivatives in Improving Insulin Resistance.

Insulin resistance is a core pathological link in metabolic diseases such as type 2 diabetes, and its prevention and treatment are current research hotspots. Quercetin, a natural flavonoid, has significant potential to improve insulin resistance through its anti-inflammatory, antioxidant, and metabolic regulatory activities. This review systematically examines literature published between 2020 and 2025 from the PubMed, Web of Science, and Scopus databases, focusing on original mechanistic studies in cellular and animal models of insulin resistance. Our synthesis reveals two mechanistic clusters: quercetin directly activates insulin signaling via the insulin receptor substrate 1/Phosphatidylinositol 3-kinase /Protein Kinase B pathway, enhances muscle glucose uptake through AMP-activated protein kinase-dependent glucose transporter 4 translocation. Indirect mechanisms include gut microbiome modulation with increased short-chain fatty acid production, suppresses hepatic inflammation and targeting of transcription factors. Critically, a clear efficacy hierarchy among derivatives was identified: glycosides show superior bioavailability compared to the aglycone, while methylated derivatives exhibit enhanced stability but divergent effects on peroxisome proliferator-activated receptor γ signaling. Major unresolved challenges include the low oral bioavailability of quercetin aglycone, the lack of systematic structure-activity relationship models, and the absence of rigorous human trials. The review concludes that chemical derivatization and advanced delivery systems offer promising strategies, but clinical translation requires an integrated framework combining systematic structure-activity profiling, mechanistic target selection, and validated human studies.