Chemical activation of mitochondrial ClpP to modulate energy metabolism of CD4+ T cell for inflammatory bowel diseases treatment

Jiangnan Zhang; Yunhan Jiang; Dongmei Fan; Zhiqiang Qiu; Xinlian He; Song Liu; Linjie Li; Zhengyi Dai; Lidan Zhang; Ziyi Shu; Lili Li; Hu Zhang; Tao Yang; Youfu Luo

doi:10.1016/j.xcrm.2024.101840

Chemical activation of mitochondrial ClpP to modulate energy metabolism of CD4⁺ T cell for inflammatory bowel diseases treatment

Cell Rep Med. 2024 Nov 23:101840. doi: 10.1016/j.xcrm.2024.101840. Online ahead of print.

Authors

Jiangnan Zhang¹, Yunhan Jiang², Dongmei Fan², Zhiqiang Qiu¹, Xinlian He¹, Song Liu¹, Linjie Li¹, Zhengyi Dai¹, Lidan Zhang¹, Ziyi Shu¹, Lili Li³, Hu Zhang³, Tao Yang⁴, Youfu Luo⁵

Affiliations

¹ State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China.
² Institute of Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China.
³ Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, China; Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu 610041, China; Laboratory of Inflammatory Bowel Disease, Institute of Immunology and Inflammation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China.
⁴ State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China; Institute of Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address: yangtao@wchscu.cn.
⁵ State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address: luo_youfu@scu.edu.cn.

PMID: 39626672
DOI: 10.1016/j.xcrm.2024.101840

Abstract

Inflammatory bowel disease (IBD) is an autoimmune disorder, and despite the availability of multiple Food and Drug Administration (FDA)-approved therapies, current clinical needs remain unmet. In this study, we find that caseinolytic protease P (ClpP) expression is markedly upregulated in colonic tissues from IBD patients and preclinical colitis models, particularly in CD4⁺ T cells. Subsequently, a small molecule, namely NCA029, is identified, and its therapeutic efficacy and mechanism of action are investigated both in vitro and in vivo. Oral administration of NCA029 significantly alleviates symptoms associated with dextran sulfate sodium (DSS)-induced acute and interleukin (IL)-10-deficient chronic colitis. The effects of NCA029 are largely dependent on its selective binding to ClpP in CD4⁺ T cells, thereby mitigating inflammation and restoring intestinal barrier function. Furthermore, NCA029 activates ClpP to promote oxidative phosphorylation (OXPHOS) inhibition and concomitantly modulate the Th17/Treg balance. In conclusion, our study develops a therapeutic strategy for treating IBD through the chemical activation of ClpP.

Keywords: ClpP; OXPHOS; inflammatory bowel diseases; mitochondrial.