{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T06:24:23Z","timestamp":1787293463817,"version":"build-2736575974"},"reference-count":30,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T00:00:00Z","timestamp":1787270400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"\n Background and aims<\/jats:title>\n Inflammatory stimuli drive metabolic reprogramming in\u00a0macrophages, supplying energy, reducing equivalents, and methyl donors required for the production of inflammatory mediators such as IL-1\u03b2; 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.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n 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\u00a0assess\u00a0nicotinamide adenine dinucleotide phosphate (NADPH) and adenosine triphosphate (ATP) generation. S-adenosylmethionine (SAM) and cytokine levels\u00a0were measured by enzyme-linked immunosorbent assay, and epigenetic regulation at the\n Il1b<\/jats:italic>\n promoter was examined by chromatin immunoprecipitation-qPCR and immunoblotting. A murine full-thickness skin wound model with macrophage depletion was used for\n in vivo<\/jats:italic>\n validation.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n 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\n Il1b<\/jats:italic>\n promoter, thereby repressing\n Il1b<\/jats:italic>\n transcription. These effects were reversed by exogenous SAM supplementation. Macrophages exhibited a metabolic bottleneck associated with low mannose phosphate isomerase (\n Mpi<\/jats:italic>\n ) expression. Consistently,\n Mpi<\/jats:italic>\n overexpression reversed the D-mannose-induced reductions in ATP and SAM levels, as well as\n Il1b<\/jats:italic>\n expression. Topical D-mannose also lowered SAM and IL-1\u03b2 levels in wound tissues and accelerated wound healing\n in vivo<\/jats:italic>\n .\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n 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.<\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1895029","type":"journal-article","created":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T05:37:45Z","timestamp":1787290665000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["D-mannose blocks S-adenosylmethionine generation to suppress macrophage IL-1\u03b2 expression"],"prefix":"10.3389","volume":"17","author":[{"given":"Yingyi","family":"Chen","sequence":"first","affiliation":[{"name":"Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junji","family":"Xu","sequence":"additional","affiliation":[{"name":"College of Stomatology, Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing Medical University","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingfei","family":"Fu","sequence":"additional","affiliation":[{"name":"Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Du","sequence":"additional","affiliation":[{"name":"Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziqing","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, School of Medicine, Case Western Reserve University","place":["Cleveland, OH, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minfeng","family":"Wang","sequence":"additional","affiliation":[{"name":"Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University","place":["Beijing, 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