Zhu Qingqing, Zeng Chengcheng, Peng Wu, Chen Huiting, Huang Hongli, Zhou Yongjian, Huang Chen, Zhao Chong
Department of Gastroenterology, the Second Affiliated Hospital, School of Medical, South China University of Technology, Guangzhou, Guangdong 510180, China; Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, Guangzhou 510180, China.
Department of Gastroenterology, the Second Affiliated Hospital, School of Medical, South China University of Technology, Guangzhou, Guangdong 510180, China; Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, Guangzhou 510180, China.
Int Immunopharmacol. 2025 Aug 28;161:115068. doi: 10.1016/j.intimp.2025.115068. Epub 2025 Jun 11.
Lovastatin, a pleiotropic cholesterol-lowering statin, possesses anti-inflammatory and immunomodulatory properties, yet its role in inflammatory bowel disease (IBD) remains unclear. This study investigates the anti-inflammatory effects of lovastatin in a dextran sulfate sodium (DSS)-induced colitis mouse model. We hypothesized that lovastatin alleviates colitis by modulating macrophage polarization via the PPARγ-NF-κB pathway. In vivo, lovastatin treatment mitigated the pathological features associated with colitis, such as body weight loss, disease activity index, colon length shortening, and colonic damage, and restoring the integrity of the intestinal mucosal barrier by preserving goblet cells and increasing tight junction proteins. Furthermore, lovastatin induced a shift in the macrophage phenotype from pro-inflammatory M1 macrophages to anti-inflammatory M2 macrophages, and downregulated M1-associated cytokines while upregulating M2 markers. RNA-seq revealed that PPARγ and NF-κB pathway may be involve in the regulation of macrophage polarization by lovastatin. In vitro, lovastatin dose-dependently inhibited LPS-induced M1 polarization in RAW264.7 cells and promoted M2 polarization via PPARγ activation, which suppressed NF-κB nuclear translocation. Mechanistically, PPARγ inhibition (GW9662) abolished lovastatin's effects, confirming PPARγ-NF-κB crosstalk. These findings demonstrate that lovastatin ameliorates colitis by rebalancing macrophage polarization through PPARγ-mediated NF-κB suppression, supporting its repurposing as a potential IBD therapy.
洛伐他汀是一种具有多种作用的降胆固醇他汀类药物，具有抗炎和免疫调节特性，但其在炎症性肠病（IBD）中的作用仍不清楚。本研究调查了洛伐他汀在葡聚糖硫酸钠（DSS）诱导的结肠炎小鼠模型中的抗炎作用。我们假设洛伐他汀通过PPARγ-NF-κB途径调节巨噬细胞极化来减轻结肠炎。在体内，洛伐他汀治疗减轻了与结肠炎相关的病理特征，如体重减轻、疾病活动指数、结肠长度缩短和结肠损伤，并通过保留杯状细胞和增加紧密连接蛋白来恢复肠黏膜屏障的完整性。此外，洛伐他汀诱导巨噬细胞表型从促炎性M1巨噬细胞向抗炎性M2巨噬细胞转变，下调M1相关细胞因子，同时上调M2标志物。RNA测序显示PPARγ和NF-κB途径可能参与洛伐他汀对巨噬细胞极化的调节。在体外，洛伐他汀剂量依赖性地抑制RAW264.7细胞中LPS诱导的M1极化，并通过激活PPARγ促进M2极化，从而抑制NF-κB核转位。机制上，PPARγ抑制（GW9662）消除了洛伐他汀的作用，证实了PPARγ-NF-κB的相互作用。这些发现表明，洛伐他汀通过PPARγ介导的NF-κB抑制来重新平衡巨噬细胞极化，从而改善结肠炎，支持将其重新用作潜在的IBD治疗药物。
