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Beta-hydroxybutyrate (BHB), a major ketone body, acts as a key regulator of intestinal epithelial regeneration. Its metabolic dysregulation has been implicated in impaired cell proliferation and the maintenance of intestinal stem cells (ISCs). However, the dynamic regulatory mechanisms underlying BHB fluctuation during burn sepsis-induced intestinal injury remain elusive. In this study, we demonstrate that TIGAR expression is markedly reduced in small intestinal crypts of burn sepsis mice. TIGAR deficiency substantially diminishes BHB production and compromises cell proliferation and ISC self-renewal capacity. Mechanistically, the 1-131 domain of TIGAR orchestrate dual functionality: it acts as a mitochondrial targeting signal to direct TIGAR localization and competitively binds the ketogenic enzyme HMGCL, thereby inhibiting its interaction with the E3 ubiquitin ligase Park2. This spatial interference blocks Park2-mediated K48-linked ubiquitination and proteasomal degradation of HMGCL, and stabilizing HMGCL to enhance BHB synthesis. Elevated BHB induces \u03b2-hydroxybutyrylation at lysine 335 of \u03b2-catenin, which facilitates \u03b2-catenin nuclear translocation and strengthens its interaction with TCF4, therefore driving cell proliferation and ISC self-renewal, ultimately maintaining intestinal epithelial regeneration. Collectively, this study identifies a novel role of TIGAR in maintaining intestinal barrier regeneration by promoting ketone body production. This previously unexplored mechanism of TIGAR may serve as a critical compensation for the treatment of burn-related gut barrier dysfunction.<\/jats:p>","DOI":"10.1038\/s41419-026-08486-7","type":"journal-article","created":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T02:26:24Z","timestamp":1771467984000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["TIGAR maintains intestinal epithelial regeneration by stabilizing HMGCL and promoting \u03b2-catenin \u03b2-hydroxybutyrylation in burn-induced sepsis"],"prefix":"10.1038","volume":"17","author":[{"given":"Panyang","family":"Zhang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dan","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Wei","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sen","family":"Su","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xule","family":"Zha","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoyan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ting","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qianying","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qian","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhongwei","family":"Bao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shijun","family":"Fan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lin","family":"Xia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-0658-6979","authenticated-orcid":false,"given":"Xi","family":"Peng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,2,19]]},"reference":[{"key":"8486_CR1","doi-asserted-by":"publisher","first-page":"1041","DOI":"10.1093\/jbcr\/irae049","volume":"45","author":"GP Dobson","year":"2024","unstructured":"Dobson GP, Morris JL, Letson HL. 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