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However, the underlying mechanisms are not fully understood, and their potential for translational clinical application needs further evaluation. In the present study, through single\u2010cell RNA sequencing (scRNA\u2010seq), transcriptomic profiles in both na\u00efve and BLP\u2010trained bone marrow\u2010derived macrophages (BMDMs) during\n                    <jats:italic>Staphylococcus aureus<\/jats:italic>\n                    infection are analyzed, and 13 distinct BMDM subpopulations are identified. Notably, BLP\u2010trained tolerance initiates the emergence of two novel BMDM subpopulations, C5 and C7, characterized by increased antibacterial gene expression and enhanced anti\u2010inflammatory and antioxidative stress abilities. Moreover, BLP\u2010trained BMDMs demonstrate activation of the NRF2 signaling pathway, thereby augmenting an antioxidative stress response and mitigating oxidative stress\u2010induced cell damage and ferroptosis, while undergoing metabolic reprogramming characterized by enhanced glycolysis and oxidative phosphorylation pathways,\u00a0together with increased anti\u2010inflammatory metabolites. Critically, in vivo adoptive transfer of BLP\u2010trained BMDMs protects mice against sepsis\u2010associated lethality by attenuating systemic inflammatory response, accelerating bacterial clearance, and alleviating organ damage. Collectively, the present study presents a single\u2010cell atlas of murine BMDMs at rest and under\n                    <jats:italic>S. aureus<\/jats:italic>\n                    infection following BLP training, which reveals novel mechanisms of BLP training\u2010altered macrophage immunity and identifies macrophage subpopulations responsible for an enhanced resistance to infection, thus offering new preventive and therapeutic strategies for sepsis.\n                  <\/jats:p>","DOI":"10.1002\/advs.202417142","type":"journal-article","created":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T18:15:23Z","timestamp":1761070523000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Exploring Functionally Enhanced BLP\u2010Trained Macrophage Subpopulations in\n                    <i>S. 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