ArticleFrontiers in immunology2026
Identification of gemilukast as a bifunctional molecule with lipid-lowering and anti-inflammatory activities.
Article in Frontiers in immunology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Background: Cardiovascular disease is driven by the interplay between dyslipidemia and chronic inflammation. However, most current therapies mainly focus on lipid lowering, leaving substantial residual inflammatory risk and underscoring the need for agents that can address both dyslipidemia and inflammation to reduce cardiometabolic risk. Here, we evaluated whether gemilukast, a cysteinyl leukotriene receptor antagonist, could serve as a bifunctional agent with lipid-lowering and anti-inflammatory activities. Methods: Intestinal cholesterol absorption was assessed using mixed-micelle solubilization and Caco-2 uptake assays. Anti-inflammatory activity was evaluated in LPS-stimulated RAW 264.7 macrophages by cytokine production and macrophage polarization, with PI3K/AKT signaling examined by Western blotting. Lipid-lowering and anti-inflammatory effects were further validated in an acute hyperlipidemia rat model and the high-fat diet (HFD) induced hyperlipidemia mouse model. Results: In Caco-2 cells, gemilukast inhibited cholesterol uptake in a concentration-dependent manner, achieving 51.6% inhibition at 10 μM versus vehicle and showing stronger inhibition than ezetimibe (50 μM). In a mixed-micelle assay, gemilukast reduced micellar cholesterol solubility by 41.5%, supporting impaired intestinal cholesterol incorporation. In LPS-stimulated RAW 264.7 macrophages, gemilukast decreased TNF-α, IL-1β, and IL-6, promoted M1-to-M2 repolarization, and was accompanied by reduced PI3K/AKT phosphorylation. Conclusion: Gemilukast exhibits dual lipid-lowering and anti-inflammatory activities. These effects are linked to reduced intestinal cholesterol uptake and macrophage reprogramming with PI3K/AKT signaling modulation. These findings provide proof-of-concept that a clinically developed leukotriene receptor antagonist can be repurposed as an immunometabolic bifunctional scaffold to address dyslipidemia with residual inflammatory risk.
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