{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T10:57:31Z","timestamp":1794049051738,"version":"4.8.0"},"reference-count":109,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T00:00:00Z","timestamp":1771545600000},"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":"<jats:p>Sepsis is a complex condition marked by significant dysregulation of immune and metabolic processes, leading to multi-organ failure. Macrophages, key mediators of immune activity, demonstrate functional flexibility by switching between pro- and anti-inflammatory phenotypes in response to inflammatory and metabolic signals in their local environment. During sepsis, pathogen-derived signals activate host defense responses that impair intercellular oxygen transport, increase oxygen consumption by immune cells within inflamed tissues, and promote a metabolic transition toward aerobic glycolysis. This metabolic transition supports immune defense mechanisms, and the metabolic by-products further regulate immune activation through feedback in key signaling cascades, promoting a transition toward tolerance during the resolution phase. Since mitochondria are central hubs for cellular energy homeostasis, they play a crucial role in this process. Mitochondrial dysfunction and metabolic changes are now recognized as major contributors to the progression of sepsis. The accumulation of mitochondria-derived metabolites can further modulate immune signaling pathways, actively influencing macrophage function. Therefore, this review emphasizes the crosstalk between macrophage polarization and mitochondrial changes, with a focus on new molecular insights and the potential of mitochondrial pathways as biomarkers or therapeutic targets. These concepts provide a foundation for advancing both experimental research and clinical applications, potentially guiding future interventions to better manage sepsis and its associated mortalities.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1692597","type":"journal-article","created":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T05:21:16Z","timestamp":1771564876000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Crosstalk of mitochondrial dysfunction and macrophage polarization in 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