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Lactate exerts multiple pathophysiological effects in the aftermath of TBI. This study aimed to elucidate the role of lactate\u2010mediated lactylation in these post\u2010TBI pathological processes. Here, we found that the level of lactylation was elevated in brain tissues after TBI and predominantly in neurons. Proteomic analysis revealed that mitochondrial proteins underwent significant lactylation. Lactylation at the K112 site of fumarate hydratase (FH) induced mitochondrial damage and tricarboxylic acid (TCA) cycle dysfunction. Accumulation of fumarate and release of mitochondrial DNA (mtDNA) activated the cGAS\u2010STING pathway of the innate immune response, thereby exacerbating neuroinflammation and cerebral edema. Furthermore, AARS2 and SIRT3 were identified as the respective \u201cwriter\u201d and \u201ceraser\u201d of FH K112 lactylation. The short peptide Pep\u2010K112 targeted and inhibited lactylation at the FH K112 site, ameliorating mitochondrial function and alleviating neuroinflammation and cerebral edema. These findings demonstrate the regulatory role of lactylation in the pathological progression of TBI and suggest that targeting FH lactylation may be a promising strategy for TBI treatment.<\/jats:p>","DOI":"10.1002\/advs.77698","type":"journal-article","created":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T18:00:31Z","timestamp":1790532031000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Fumarate Hydratase Lactylation Exacerbates Traumatic Brain Injury Pathology via Mitochondrial Dysfunction and Neuroinflammation"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7857-6876","authenticated-orcid":false,"given":"Yang","family":"Tian","sequence":"first","affiliation":[{"name":"Department of Neurosurgery Tangdu Hospital Fourth Military Medical University  Xi'an 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