D-mannose blocks S-adenosylmethionine generation to suppress macrophage IL-1β expression.

Background and aims: Inflammatory stimuli drive metabolic reprogramming in macrophages, supplying energy, reducing equivalents, and methyl donors required for the production of inflammatory mediators such as IL-1β; however, metabolic strategies to regulate this pathway remain unclear. Here, we aimed to define the mechanism by which D-mannose suppresses one-carbon metabolism in inflammatory macrophages and thereby epigenetically restrains inflammatory responses. Methods: Untargeted metabolomics was used to define the global metabolic effects of D-mannose in inflammatory macrophages. 6-phosphogluconate dehydrogenase activity and real-time ATP rate assays were performed to assess nicotinamide adenine dinucleotide phosphate (NADPH) and adenosine triphosphate (ATP) generation. S-adenosylmethionine (SAM) and cytokine levels were measured by enzyme-linked immunosorbent assay, and epigenetic regulation at the Results: D-mannose suppressed metabolic flux through glycolysis, the tricarboxylic acid (TCA) cycle, and the pentose phosphate pathway, resulting in reduced ATP and NADPH production. This metabolic restriction impaired one-carbon metabolism, decreased SAM abundance, and reduced histone H3 lysine 36 trimethylation enrichment at the Conclusions: D-mannose suppresses macrophage pro-inflammatory transcription through a one-carbon metabolism-epigenetic axis, supporting its potential as a metabolism-targeted strategy for inflammatory wound repair.