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Galectin-3-binding protein (LGALS3BP) is a secreted glycoprotein implicated in inflammation and metabolic disorders. Elevated LGALS3BP levels are associated with MASLD and type 2 diabetes (T2D), but its role in IR remains unclear.Methods: LGALS3BP-deficient models were used to investigate its role in IR and inflammation. Glucose metabolism and insulin signaling were assessed in high-fat diet (HFD)-fed mice. Hepatic cell lines were employed to evaluate the direct effects of LGALS3BP on insulin signaling and inflammation. Mechanistic insights were obtained through RNA sequencing, structural modeling, immunoprecipitation, and protein\/gene expression analyses.Results: LGALS3BP deficiency improved insulin sensitivity in HFD-fed mice by enhancing glucose tolerance, lowering serum glucose and insulin, and increasing hepatic insulin signaling, without altering lipid accumulation. In vitro, LGALS3BP deficiency enhanced insulin signaling and suppressed gluconeogenesis, whereas recombinant LGALS3BP impaired insulin signaling and upregulated gluconeogenesis. RNA sequencing revealed activation of Toll-like receptor 2 (TLR2) and nuclear factor-kappa B (NF-\u03baB) pathways by LGALS3BP. Immunoprecipitation confirmed a direct interaction between LGALS3BP and TLR2, leading to inhibitor kappa kinase (IKK)\/NF-\u03baB activation and increased insulin receptor substrate-1 (IRS1) serine phosphorylation, a key inhibitory modification in IR. Furthermore, LGALS3BP deficiency attenuated hepatic fibrosis under chronic HFD, accompanied by downregulated inflammatory signaling pathways.Conclusion: LGALS3BP contributes to IR through inflammatory responses, particularly via TLR2-IKK\u03b1\/\u03b2 signaling that regulates IRS1 serine phosphorylation. LGALS3BP deficiency improves insulin sensitivity and reduces inflammation, suggesting that targeting LGALS3BP may represent a potential therapeutic strategy for metabolic disorders such as T2D and MASLD.<\/jats:p>","DOI":"10.3803\/enm.2025.2448","type":"journal-article","created":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T05:03:15Z","timestamp":1761109395000},"page":"121-137","update-policy":"https:\/\/doi.org\/10.3803\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["LGALS3BP Induces Insulin Resistance via TLR2-IKK\u03b1\/\u03b2 Pathway-Mediated IRS1 Serine 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