ORIGINAL RESEARCH article
Front. Immunol.
Sec. Inflammation
Identification of gemilukast as a bifunctional molecule with lipid-lowering and anti-inflammatory activities
Yuanyuan Liu 1
Yixiao Wang 2
Rufei Wang 2
Qingshan Yang 1
Guojun Pan 2
Renshuai Zhang 2
1. First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
2. Shandong First Medical University, Jinan, China
Select one of your emails
You have multiple emails registered with Frontiers:
Notify me on publication
Please enter your email address:
If you already have an account, please login
You don't have a Frontiers account ? You can register here
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.
Summary
Keywords
cholesterolabsorption, dual-action agent, gemilukast, Hyperlipidemia, Inflammation
Received
03 November 2025
Accepted
17 February 2026
Copyright
© 2026 Liu, Wang, Wang, Yang, Pan and Zhang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Renshuai Zhang
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.