3-Hydroxypropionic acid converts inflammatory macrophage glycolysis into mitochondrial oxidation through GAPDH...

Macrophages dynamically reprogram their metabolic states in response to environmental stimuli, thereby exerting distinct immune functions. In our preliminary study, a gut microbiota-derived metabolite, 3-hydroxypropionic acid (3-HPA), is increased in chronic inflammation and generates cysteine carboxyethylated neoantigens. However, the role of such metabolite-induced modification in regulating the function of macrophages remains obscure. Here, we show that 3-HPA alleviates inflammation in a mouse model of sepsis and inhibits the macrophage inflammatory response. Mechanistically, 3-HPA induces glyceraldehyde-3-phosphate dehydrogenase (GAPDH) carboxyethylation, which promotes GAPDH degradation via the ubiquitin-proteasome pathway, thereby suppressing its enzymatic activity and expression to inhibit glycolysis. Concomitantly, reduced GAPDH activity elevates the NAD⁺/NADH ratio, which enhances mitochondrial oxidation by upregulating arginine biosynthesis and the TCA cycle pathway. Overall, our research reveals the mechanism by which GAPDH carboxyethylation mediates metabolic reprogramming and regulates inflammation during inflammatory macrophage activation.