{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T17:34:22Z","timestamp":1791653662465,"version":"4.3.4"},"reference-count":137,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T00:00:00Z","timestamp":1779408000000},"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>Innate immune cells, undergo profound metabolic changes in critical illnesses. In both, acute-on-chronic liver failure (ACLF) and sepsis, these alterations underpin the paradoxical coexistence of hyperinflammation and immune dysfunction. Here, we present a comparative framework to examine how immune metabolic circuits are reshaped across these two syndromes. We focus primarily on neutrophil function while also considering contributions from other immune cell types, highlighting shared pathways, divergent mechanisms, and their clinical implications. We first delineate shared features of neutrophil activation in critical illness, including glycolysis-driven metabolic reprogramming, excessive reactive oxygen species (ROS) generation, and neutrophil extracellular trap (NET) formation, all processes that amplify tissue injury and propagate systemic inflammation. However, fundamental differences emerge in the baseline immune state, trajectory, and underlying immunometabolic programming of the two diseases. Sepsis arises as an acute insult in a previously homeostatic immune system, triggering a rapid transition from hyperactivation to mitochondrial dysfunction and eventual metabolic exhaustion. In contrast, ACLF develops on a background of chronic liver disease, where immune cells are already primed and metabolically stressed, resulting in a constrained and dysfunctional response from the outset. By placing ACLF and sepsis side by side, this review highlights the metabolic regulation of innate immunity, particularly neutrophils, as both a unifying principle and a disease-specific vulnerability. This comparative perspective deepens mechanistic understanding and provides a framework for precision immunometabolic interventions in critical illness.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1828801","type":"journal-article","created":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T04:41:45Z","timestamp":1779424905000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Neutrophil immunometabolism in ACLF and sepsis: mechanisms, dysfunction, and therapeutic opportunities"],"prefix":"10.3389","volume":"17","author":[{"given":"Sonali","family":"Mukherjee","sequence":"first","affiliation":[{"name":"Department of Biochemistry, All India Institute of Medical Sciences","place":["New Delhi, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takhellambam","family":"Malemnganba","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, All India Institute of Medical 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