Chen Qingge, Li Xiaodong, Ma Jialu, Li Wenguan, Wang Xiongbiao, Ni Zhenhua
Department of Respiratory Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China.
Center for Systems Pharmacokinetics, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Biochem Pharmacol. 2025 Sep;239:117077. doi: 10.1016/j.bcp.2025.117077. Epub 2025 Jun 23.
The overexpression of mucin 5AC (MUC5AC) induced by interferon-beta (IFN-β) plays a critical role in airway mucus hypersecretion and contributes to the mortality associated with coronavirus disease 2019 (COVID-19) patients. Epigallocatechin gallate (EGCG), a polyphenol derived from green tea, has demonstrated potential as a therapeutic agent for the treatment of coronavirus-related diseases. This study aimed to investigate the regulatory effects of EGCG on IFN-β-induced MUC5AC overexpression and to elucidate its underlying molecular mechanisms. We found that IFN-β-induced MUC5AC overexpression was associated with the activation of the signal transducer and activator of transcription 1 (STAT1) and extracellular signal-regulated kinase (ERK) signaling pathways. The use of STAT1 or ERK inhibitors significantly attenuated IFN-β-induced MUC5AC overexpression. EGCG treatment markedly inhibited IFN-β-induced MUC5AC overexpression and suppressed activation of the STAT1 and ERK signaling pathways. Subsequent research revealed that EGCG binds to Janus kinase 1 (JAK1) and inhibits its kinase activity, leading to reduced phosphorylation of STAT1 and ERK. The use of JAK1 inhibitors reproduced the effects observed with EGCG treatment. Structural analysis indicated that the methyl gallate of the EGCG molecule was crucial for its inhibitory activity. In vivo studies demonstrated that EGCG effectively suppressed IFN-β-induced mucus hypersecretion and MUC5AC overexpression, along with inhibition of the associated signaling pathways. In conclusion, EGCG inhibits IFN-β-induced MUC5AC overexpression by suppressing JAK1 kinase activity, thereby blocking activation of the STAT1 and ERK signaling pathways.
干扰素-β（IFN-β）诱导的粘蛋白5AC（MUC5AC）过表达在气道黏液高分泌中起关键作用，并与2019冠状病毒病（COVID-19）患者的死亡率相关。表没食子儿茶素没食子酸酯（EGCG）是一种从绿茶中提取的多酚，已显示出作为治疗冠状病毒相关疾病的治疗剂的潜力。本研究旨在探讨EGCG对IFN-β诱导的MUC5AC过表达的调节作用，并阐明其潜在的分子机制。我们发现，IFN-β诱导的MUC5AC过表达与信号转导和转录激活因子1（STAT1）和细胞外信号调节激酶（ERK）信号通路的激活有关。使用STAT1或ERK抑制剂可显著减弱IFN-β诱导的MUC5AC过表达。EGCG处理显著抑制IFN-β诱导的MUC5AC过表达，并抑制STAT1和ERK信号通路的激活。随后的研究表明，EGCG与Janus激酶1（JAK1）结合并抑制其激酶活性，导致STAT1和ERK的磷酸化减少。使用JAK1抑制剂可重现EGCG处理所观察到的效果。结构分析表明，EGCG分子的没食子酸甲酯对其抑制活性至关重要。体内研究表明，EGCG有效抑制IFN-β诱导的黏液高分泌和MUC5AC过表达，同时抑制相关信号通路。总之，EGCG通过抑制JAK1激酶活性来抑制IFN-β诱导的MUC5AC过表达，从而阻断STAT1和ERK信号通路的激活。
