Abstract

Carboxyamidotriazole (CAI), an inhibitor of mitochondrial complex I, demonstrates anti-inflammatory and anti-tumor properties. While effective against colitis, its potential link to macrophage metabolism in colitis and colitis-associated colorectal cancer (CAC) remained unexplored. This study investigates the role of CAI and its association with macrophage metabolic states in these conditions. In the acute phase, CAI alleviates dextran sulfate sodium (DSS)-induced colitis, which is accompanied by suppressed IL-1β expression in pro-inflammatory macrophages. As a mitochondrial respiratory chain inhibitor, CAI treatment is associated with metabolic alterations characterized by accumulated α-ketoglutarate (α-KG) and decreased succinate and acetyl-CoA. This rewiring correlates with reduced hypoxia-inducible factor 1-alpha (HIF-1α) and decreased H3K27 acetylation (H3K27ac) at the Il1b locus. In the azoxymethane (AOM)/DSS model of CAC, we observed CD86+CD206+ mixed-phenotype macrophages during chronic inflammation. In CD206+ macrophages, CAI treatment is linked to the inhibition of oxidative phosphorylation (OXPHOS) and fatty acid β-oxidation (FAO), concomitant with reactive oxygen species (ROS) reduction and impaired Stat6 phosphorylation. Concurrently, accumulated fatty acids are associated with increased PPARγ signaling. This coordinated modulation of Stat6 and PPARγ pathways correlates with sustained anti-inflammatory effects, as well as with reduced expression of pro-fibrotic and pro-angiogenic mediators. Our findings position CAI's effects in colitis and CAC alongside dynamic changes in macrophage metabolism. This work provides new insights into targeting metabolic pathways in inflammatory carcinogenesis.