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While their role as acute adjuvants is well-documented, the innate immune memory (trained immunity) signatures induced by Mn2+ remain unexplored. Using an in vitro priming-rest-challenge model, we demonstrate that transient Mn2+ stimulation induces a persistent anti-inflammatory state in bone marrow\u2013derived macrophages (BMDMs). Unlike the immediate proinflammatory burst associated with Mn2+, Mn2+-trained BMDMs displayed a stable reduction in Il6, Il1b, Il12a, and Nos2 expression upon secondary LPS or LPS\u202f+\u202fIFN-\u03b3 challenge. Furthermore, Mn2+ training enhanced IL-4\u2013driven Arg1 induction and suppressed MHC class II surface expression, antigen presentation pathways, and phagocytic capacity against Candida albicans. Mechanistically, this functional attenuation was independent of glycolysis but correlated with a broad downregulation of lipid metabolic pathways. These findings reveal a lineage-specific regulatory \u201cbrake\u201d induced by manganese, providing critical insights for its application in immunotherapy.<\/jats:p>","DOI":"10.1093\/jimmun\/vkag267","type":"journal-article","created":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T05:24:12Z","timestamp":1792041852000},"source":"Crossref","is-referenced-by-count":0,"title":["Transient manganese exposure reprograms bone marrow\u2013derived macrophages toward a stable anti-inflammatory memory state"],"prefix":"10.1093","volume":"215","author":[{"given":"Yang","family":"Luo","sequence":"first","affiliation":[{"name":"State Key Laboratory of Cellular Stress Biology, School of Life Science, Faculty of Medicine and Life Sciences, Xiamen University , Xiamen,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Cheng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cellular Stress Biology, School of Life Science, Faculty of Medicine and Life Sciences, Xiamen University , Xiamen,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cellular Stress Biology, School of Life Science, Faculty of Medicine and Life Sciences, Xiamen University , Xiamen,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linying","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cellular Stress Biology, School of Life Science, Faculty of Medicine and Life Sciences, Xiamen University , Xiamen,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1251-8774","authenticated-orcid":false,"given":"Shih-Chin","family":"Cheng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cellular Stress Biology, School of Life Science, Faculty of Medicine and Life 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