Qiu Jiahao, Fu Lihong, Xue Yan, Yang Yilan, Qiao Fengjie, Zhu Wanchun, Gao Yating, Fang Miao, Liu Yufei, Gao Zhujun, Guan Yunfeng, Gao Yueqiu, Zhang Xin, Shang Zhi
Institute of Infectious Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Laboratory of Cellular Immunity, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Front Pharmacol. 2025 Apr 1;16:1563561. doi: 10.3389/fphar.2025.1563561. eCollection 2025.
Gallic acid (GA), a natural organic phenolic compound, is an abundant plant food bioactive substance present in many medicinal herbs. GA has anti-oxidative, anti-inflammatory and anticancer activities on multiple metabolic disorders. The present study was carried out to uncover the alleviating effects of GA on metabolic dysfunction-associated steatohepatitis (MASH) and the underlying mechanisms of its action. In this study, a mouse model of MASH induced by high-fat and high-carbohydrate diet was used to test the impact of GA on metabolic disorders. We found that GA administration attenuated obesity and fatty liver, relieved insulin resistance, and mitigated hepatic steatosis, inflammation and liver injury. Transcriptome sequencing (RNA-seq) of mouse liver tissues identified 154 differentially expressed genes (DEGs) among the NCD, HFHC, and GA groups. Bioinformatic analysis of these DEGs revealed significant enrichment in lipid metabolism function and the PPARγ signaling pathway, which were further validated. Overexpression of PPARγ significantly reduced the therapeutic effect of GA both and . Notably, the transcription factor interferon regulatory factor 6 (IRF6), a protective factor in metabolic stress, which was predicted as the upstream regulator, was significantly upregulated by GA. Furthermore, it was verified that GA's anti-lipid deposition effect depends on the negative regulation of IRF6 on PPARγ using knocking-down strategy. Taken together, GA increases hepatic IRF6 expression, which mitigates lipid accumulation of hepatocytes and subsequent liver damage via inhibiting the PPARγ signaling pathway. These findings suggest a novel strategy for MASH management based on pharmacological intervention with GA.
没食子酸（GA）是一种天然有机酚类化合物，是许多药草中丰富的植物性食物生物活性物质。GA对多种代谢紊乱具有抗氧化、抗炎和抗癌活性。本研究旨在揭示GA对代谢功能障碍相关脂肪性肝炎（MASH）的缓解作用及其潜在作用机制。在本研究中，使用高脂高碳水化合物饮食诱导的MASH小鼠模型来测试GA对代谢紊乱的影响。我们发现，给予GA可减轻肥胖和脂肪肝，缓解胰岛素抵抗，并减轻肝脏脂肪变性、炎症和肝损伤。对小鼠肝脏组织进行转录组测序（RNA-seq），在正常对照饮食（NCD）、高脂高碳水化合物饮食（HFHC）和GA组中鉴定出154个差异表达基因（DEG）。对这些DEG进行生物信息学分析，发现脂质代谢功能和PPARγ信号通路有显著富集，这进一步得到了验证。PPARγ的过表达显著降低了GA的治疗效果。值得注意的是，转录因子干扰素调节因子6（IRF6）是代谢应激中的一个保护因子，被预测为上游调节因子，被GA显著上调。此外，使用敲低策略证实了GA的抗脂质沉积作用取决于IRF6对PPARγ的负调控。综上所述，GA增加肝脏IRF6表达，通过抑制PPARγ信号通路减轻肝细胞脂质积累和随后的肝损伤。这些发现提示了一种基于GA药物干预的MASH管理新策略。
