What question did this study set out to answer?

The aim is to evaluate gemilukast as a dual-action agent targeting both lipid levels and inflammation to reduce cardiometabolic risk.

March 7, 2026Open Access

Identification of gemilukast as a bifunctional molecule with lipid-lowering and anti-inflammatory activities

Key Points

The aim is to evaluate gemilukast as a dual-action agent targeting both lipid levels and inflammation to reduce cardiometabolic risk.
Assessed cholesterol absorption in Caco-2 cells using mixed-micelle and uptake assays.
Evaluated anti-inflammatory effects in LPS-stimulated RAW 264.7 macrophages by measuring cytokine production and macrophage polarization.
Examined PI3K/AKT signaling through Western blotting.
Validated lipid-lowering effects in hyperlipidemia rat and high-fat diet mouse models.
Gemilukast inhibited cholesterol uptake by 51.6% at 10 μM in Caco-2 cells.
Reduced micellar cholesterol solubility by 41.5% in mixed-micelle assays.
Decreased pro-inflammatory cytokines in RAW 264.7 macrophages, including TNF-α, IL-1β, and IL-6.
Lowered plasma total cholesterol by 14.8% in hyperlipidemic rats and by 25.9% in HFD-fed mice, with significant reductions in inflammatory cytokines.

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. In vivo , gemilukast (10 mg/Kg) lowered plasma TC by 14.8% at 2 h after an oral lipid challenge in rats. In HFD-fed mice, gemilukast (10 mg/Kg) reduced TC by 25.9% and decreased circulating pro-inflammatory cytokines (IL-1β by 22.0%, IL-6 by 31.5%, and TNF-α by 36.0%). 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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