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

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. • ClpP expression is increased in colonic tissues of IBD patients and colitis models • Chemical activation of mitochondrial ClpP alleviates IBD symptoms • ClpP activator inhibits OXPHOS and regulates the Th17/Treg balance Zhang et al. discover that chemical activation of mitochondrial ClpP disrupts the mitochondrial respiratory chain complexes, affecting OXPHOS in CD4 + T cells. This disruption is crucial for regulating the Th17/Treg cells balance, ultimately alleviating symptoms of experimental inflammatory bowel disease (IBD).