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Identification of gemilukast as a bifunctional molecule with lipid-lowering and anti-inflammatory activities
Yuanyuan Liu1, Yixiao Wang2, Rufei Wang2
1Department of Internal Neurology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China.
Insights
Gemilukast demonstrates dual lipid-lowering and anti-inflammatory effects by reducing cholesterol absorption and modulating macrophage activity. This bifunctional agent offers a novel approach to managing dyslipidemia and residual inflammatory risk in cardiometabolic disease.
Area of Science:
- Immunometabolism
- Cardiovascular Pharmacology
- Drug Repurposing
Background:
- Cardiovascular disease (CVD) is significantly influenced by dyslipidemia and chronic inflammation.
- Current therapies primarily target lipid reduction, leaving residual inflammatory risk unaddressed.
- Novel agents are needed to combat both dyslipidemia and inflammation for reduced cardiometabolic risk.
Purpose of the Study:
- To investigate gemilukast, a cysteinyl leukotriene receptor antagonist, as a potential bifunctional agent.
- To evaluate gemilukast's capacity for both lipid-lowering and anti-inflammatory activities.
Main Methods:
- Assessed intestinal cholesterol absorption via mixed-micelle assays and Caco-2 cell uptake.
- Evaluated anti-inflammatory effects in LPS-stimulated macrophages, measuring cytokine production and polarization.
- Examined PI3K/AKT signaling pathways using Western blotting.
- Validated effects in rat and mouse models of hyperlipidemia.
Main Results:
- Gemilukast inhibited cholesterol uptake in Caco-2 cells (51.6% at 10 μM) and reduced micellar cholesterol solubility (41.5%).
- In macrophages, gemilukast decreased pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), promoted M2 polarization, and reduced PI3K/AKT phosphorylation.
- In vivo, gemilukast lowered plasma total cholesterol (TC) and reduced pro-inflammatory cytokines in hyperlipidemic models.
Conclusions:
- Gemilukast possesses significant dual lipid-lowering and anti-inflammatory properties.
- These effects are mediated by reduced intestinal cholesterol absorption and macrophage reprogramming via PI3K/AKT signaling.
- Gemilukast represents a viable repurposed agent for addressing dyslipidemia with residual inflammatory risk.
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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