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Emerging evidence suggests that hippocampal vulnerability may be linked to bioenergetic dysfunction, though its role remains poorly defined. A deeper understanding of post-TBI metabolic disturbances and their association with pathological outcomes could reveal novel therapeutic targets. In this study, we conducted functional bioenergetic assessments and multi-omics analyses on hippocampal slices using a mouse controlled cortical impact model of TBI.\u00a0Seahorse analysis revealed a significant reduction in mitochondrial oxidative phosphorylation in dentate gyrus (DG) slices at day 1 (acute phase), which recovered by day 7 (subacute phase) post-TBI. Metabolomic profiling revealed acute impairments in purine nucleotide, glucose, amino acid, and fatty acid metabolism, most of which normalized by day 7. Isotope tracing indicated enhanced octanoate-derived fatty acid oxidation (FAO) in DG slices at day 7 post-TBI. Proteomics confirmed suppressed purine metabolism at day 1 across hippocampal subregions, while FAO remained preserved at day 1 and became significantly elevated by day 7, suggesting a compensatory metabolic adaptation. Administration of sodium octanoate, a medium-chain fatty acid, at 1\u00a0h post-TBI enhanced mitochondrial respiration at 24\u00a0h, reduced microglial counts at 48\u00a0h, and attenuated neurodegeneration by day 3. These findings identify FAO enhancement as a promising metabolic strategy to restore hippocampal bioenergetics and promote neuroprotection following TBI.<\/jats:p>","DOI":"10.1007\/s12035-026-05767-2","type":"journal-article","created":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T18:52:50Z","timestamp":1772304770000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Hippocampal Bioenergetics and Metabolic Profiling Identifies Fatty Acid Oxidation as a Potential Therapeutic Target in Traumatic Brain Injury"],"prefix":"10.1007","volume":"63","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9248-7703","authenticated-orcid":false,"given":"Di","family":"Zhou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-6545-1528","authenticated-orcid":false,"given":"Mengxuan","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1101-6924","authenticated-orcid":false,"given":"Mitchell D.","family":"Kilgore","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2083-7129","authenticated-orcid":false,"given":"Yuwen","family":"Xiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-8502-6354","authenticated-orcid":false,"given":"Yingjie","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danni","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thin Yadanar","family":"Sein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0953-7800","authenticated-orcid":false,"given":"Charles","family":"Vidoudez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amin","family":"Iskender","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaby A.","family":"Moyano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren M.","family":"Dumont","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7344-7028","authenticated-orcid":false,"given":"Yinghua","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4708-9140","authenticated-orcid":false,"given":"Prasad V. 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