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

• DOI: 10.1016/j.apsb.2024.11.017
• Publication Date: 2024-11-27T00:11:30Z
• Authors: 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
• Keywords: Dual role

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