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Lipocalin\u20102 (Lcn2), an acute\u2010phase protein, regulates iron homeostasis and oxidative stress, but its impact on mitochondrial resilience remains poorly understood. Here, we investigated the role of Lcn2 in modulating mitochondrial function and hepatic stress responses in C57BL\/6\u2009J (BL6) and BALB\/c mice in LPS\u2010induced endotoxemia. Lcn2\u2010deficient (Lcn2KO) mice exhibited reduced basal respiration, maximal respiration, and spare respiratory capacity, indicating impaired mitochondrial oxidative phosphorylation. Administration of recombinant Lcn2 (rLcn2) restored mitochondrial respiration in both mouse strains under basal conditions; however, during LPS challenge, only BL6 mice partially preserved mitochondrial function, whereas BALB\/c mice remained compromised. To explore underlying mechanisms, we assessed hepatic gene expression by qRT\u2010PCR. LPS induced Acyl\u2010CoA synthetase long\u2010chain family member 4 (ACSL4) and suppressed lysophosphatidylcholine acyltransferase 3 (LPCAT3), markers associated with lipid remodeling, as well as altered antioxidant genes glutathione peroxidase 4 (GPX4) and superoxide dismutase 2 (SOD2) in both strains. rLcn2 treatment in BL6 mice normalized ACSL4 and LPCAT3 expression and enhanced antioxidant gene transcription, whereas BALB\/c mice showed minimal recovery. In BL6 mice, Lcn2 supports oxidative phosphorylation while simultaneously modulating lipid metabolism and antioxidant defenses, highlighting its integrated role in cellular adaptation to endotoxemia. Our results reveal that differential Lcn2 responsiveness contributes to inter\u2010strain variation in susceptibility to sepsis\u2010induced mitochondrial dysfunction and identify Lcn2 as a potential therapeutic target for enhancing metabolic resilience during sepsis.<\/jats:p>","DOI":"10.1002\/jcp.70205","type":"journal-article","created":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T06:00:13Z","timestamp":1782712813000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Lipocalin\u20102 Restores Mitochondrial and Antioxidant Adaptation in a Strain\u2010Specific Manner During LPS Induced Sepsis"],"prefix":"10.1002","volume":"241","author":[{"given":"Vinita","family":"Kushwaha","sequence":"first","affiliation":[{"name":"UT\u2010Microbiome Consortium, Department of Physiology &amp; Pharmacology The University of Toledo College of Medicine and Life Sciences Toledo OH 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