Loss of Sugen Kinase 495 in macrophages alleviates chronic colitis by improving mitochondrial stress.

Inflammatory bowel disease (IBD), highlighted by chronic intestinal inflammation, is an escalating global health concern. The pathogenesis of IBD is not fully understood, with DSS-induced chronic colitis in mice serving as a prevalent model, characterized by an increase in Ly6Chigh macrophages-a signature of IBD. Sugen Kinase 495 (Sgk495), also known as serine/threonine kinase 40 (STK40), is known to influence cell differentiation, has an obscure role in mitochondrial in macrophage and its molecular mechanisms. Our research demonstrates that Sgk495 exacerbates chronic colitis in mice by disrupting colon structure and function and enhancing colonic pathology. The absence of Sgk495 in macrophage cells resulted in a reduction in the proportion of Ly6Chigh macrophage. Mechanistically, Sgk495 silencing also improved mitochondrial stress by upregulated PINK1, Parkin, TOMM20 and DRP1, while reducing FOXO3a phosphorylation. Knockout of Sgk495 downregulates FOXO3a phosphorylation and improves mitochondrial stress, inhibits Ly6Chigh macrophage polarization, and alleviates chronic colonic inflammation. Sgk495 may serve as a new potential therapeutic target for IBD.