Jin Xianwei, Weng Qiaoling, Qian Kejian, Liu Fen
Department of Critical Care Medicine, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, China; Medical Innovation Center, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, China.
Department of Anesthesiology, the Second Affiliated Hospital of Nanchang University, Nanchang 330000, China.
Int Immunopharmacol. 2025 Sep 23;162:115175. doi: 10.1016/j.intimp.2025.115175. Epub 2025 Jul 12.
Acute lung injury (ALI), a severe pulmonary condition associated with sepsis, involves deterioration of alveolar and capillary endothelial cells during initial stages. Current therapeutic interventions remain insufficient.
This study investigates the therapeutic epigallocatechin gallate (EGCG) on sepsis-induced ALI and its underlying molecular mechanisms.
The effects of EGCG on M1 macrophage polarization and its glycolytic activity in sepsis models were evaluated through both in vitro and in vivo experiments. The targets of EGCG were identified using network pharmacology and molecular docking techniques, which were subsequently validated through experimental studies. The CCK-8 assay was employed to determine the optimal concentration of EGCG for maintaining the highest viability of LPS-treated RAW264.7 macrophages and bone marrow-derived macrophages (BMDMs). The sepsis models utilized included LPS-treated cell models and murine models established via cecal ligation and puncture (CLP). These models were evaluated through various biological methodologies, including qPCR, ELISA, and Western blot analysis across multiple dimensions.
EGCG effectively reduced the expression of HK2, PKM2, and iNOS, mitigating lung damage in CLP mice. Network pharmacology analysis identified the epidermal growth factor receptor (EGFR) as a primary target, associated with the HIF-1α pathway. Mechanistically, EGCG reduced p-EGFR/EGFR, suppressing the expression of HIF-1α, HK2, PKM2, and iNOS.
EGCG reduces ALI caused by sepsis by inhibiting macrophage glycolysis through the EGFR/HIF-1α signaling pathway.
急性肺损伤（ALI）是一种与脓毒症相关的严重肺部疾病，在初始阶段涉及肺泡和毛细血管内皮细胞的恶化。目前的治疗干预措施仍然不足。
本研究调查表没食子儿茶素没食子酸酯（EGCG）对脓毒症诱导的ALI的治疗作用及其潜在的分子机制。
通过体外和体内实验评估EGCG对脓毒症模型中M1巨噬细胞极化及其糖酵解活性的影响。使用网络药理学和分子对接技术鉴定EGCG的靶点，随后通过实验研究进行验证。采用CCK-8法确定维持经脂多糖（LPS）处理的RAW264.7巨噬细胞和骨髓来源巨噬细胞（BMDM）最高活力的EGCG最佳浓度。所使用的脓毒症模型包括LPS处理的细胞模型和通过盲肠结扎和穿刺（CLP）建立的小鼠模型。通过多种生物学方法对这些模型进行评估，包括qPCR、ELISA和多维度的蛋白质免疫印迹分析。
EGCG有效降低HK2、PKM2和诱导型一氧化氮合酶（iNOS）的表达，减轻CLP小鼠的肺损伤。网络药理学分析确定表皮生长因子受体（EGFR）为主要靶点，与缺氧诱导因子-1α（HIF-1α）途径相关。机制上，EGCG降低磷酸化EGFR/EGFR，抑制HIF-1α、HK2、PKM2和iNOS 的表达。
EGCG通过EGFR/HIF-1α信号通路抑制巨噬细胞糖酵解，减轻脓毒症引起的ALI。
