Dual activation of GCGR/GLP1R signaling ameliorates intestinal fibrosis via metabolic regulation of histone H3K9 lactylation in epithelial cells  

作　　者：Han Liu Yujie Hong Hui Chen Xianggui Wang Jiale Dong Xiaoqian Li Zihan Shi Qian Zhao Longyuan Zhou JiaXin Wang Qiuling Zeng Qinglin Tang Qi Liu Florian Rieder Baili Chen Minhu Chen Rui Wang Yao Zhang Ren Mao Xianxing Jiang 

机构地区：[1]Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery,School of Pharmaceutical Sciences,Sun Yat-sen University,Guangzhou 510006,China [2]State Key Laboratory for Animal Disease Control and Prevention,College of Veterinary Medicine,Lanzhou University,Lanzhou 730000,China [3]Department of Gastroenterology,the First Affiliated Hospital of Sun Yat-sen University,Guangzhou 510080,China [4]Department of Gastroenterology,Center for Immune-related Diseases,Ruijin Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China [5]Department of Inflammation and Immunity,Lerner Research Institute,Cleveland Clinic Foundation,Cleveland,OH 44195,USA [6]State Key Laboratory of Bioactive Substance and Function of Natural Medicines,Institute of Materia Medica,Chinese Academy of Medical Sciences&Peking Union Medical College,Beijing 100050,China [7]School of Life Sciences,Key Laboratory of Preclinical Study for New Drugs of Gansu Province,School of Basic Medical Sciences&Research Unit of Peptide Science,Lanzhou University,Lanzhou 730000,China

出　　处：《Acta Pharmaceutica Sinica B》2025年第1期278-295,共18页药学学报(英文版)

基　　金：supported by the National Key R&D Program of China(2023YFC2507300);the National Natural Science Foundation of China(82273761,81970483,82170537 and 82222010);the Medical Innovation and Development Project of Lanzhou University(lzuyxcx-2022-156,China).

摘　　要：Intestinal fibrosis is a significant clinical challenge in inflammatory bowel diseases,but no effective anti-fibrotic therapy is currently available.Glucagon receptor(GCGR)and glucagon-like peptide 1 receptor(GLP1R)are both peptide hormone receptors involved in energy metabolism of epithelial cells.However,their role in intestinal fibrosis and the underlying mechanisms remain largely unexplored.Herein GCGR and GLP1R were found to be reduced in the stenotic ileum of patients with Crohn’s disease as well as in the fibrotic colon of mice with chronic colitis.The downregulation of GCGR and GLP1R led to the accumulation of the metabolic byproduct lactate,resulting in histone H3K9 lactylation and exacerbated intestinal fibrosis through epithelial-to-mesenchymal transition(EMT).Dual activating GCGR and GLP1R by peptide 1907B reduced the H3K9 lactylation in epithelial cells and ameliorated intestinal fibrosis in vivo.We uncovered the role of GCGR/GLP1R in regulating EMT involved in intestinal fibrosis via histone lactylation.Simultaneously activating GCGR/GLP1R with the novel dual agonist peptide 1907B holds promise as a treatment strategy for alleviating intestinal fibrosis.

关 键 词：Glucagon receptor Glucagon-likepeptide1 receptor LACTATE GLYCOLYSIS Post translational modification Epithelial-to-mesenchymal transition Intestinal fibrosis PEPTIDE 

分 类 号：R57[医药卫生—消化系统]