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Here, the SIRT6\u2013TDO2\/KYNA\u2013mTOR axis is identified as a critical mediator of synaptic dysfunction and cognitive deficits in FGR offspring. Hippocampal excitatory neurons in FGR mice exhibit markedly reduced SIRT6 expression, and SIRT6 conditional knockout in CaMKII\u03b1\u207a neurons (\n                    <jats:italic>Sirt6<\/jats:italic>\n                    cKO) recapitulates FGR-induced synaptic and cognitive impairments. Mechanistically, SIRT6 governs synaptic plasticity and cognition via its histone deacetylase activity, independent of its ADP-ribosyltransferase function. SIRT6 deficiency increases histone H3K9 acetylation at the\n                    <jats:italic>Tdo2<\/jats:italic>\n                    promoter, enhancing kynurenine pathway flux and leading to pathological accumulation of hippocampal kynurenic acid (KYNA). Elevated KYNA suppresses AKT\/mTOR\/p70S6K1 signaling, disrupting synaptic protein synthesis. Strikingly, pharmacological TDO2 blockade, neuronal TDO2 knockdown or mTOR activation reverses synaptic and cognitive deficits in\n                    <jats:italic>Sirt6<\/jats:italic>\n                    cKO mice. Crucially, hippocampal SIRT6 overexpression in FGR mice normalizes KYNA levels, reactivates mTOR signaling, and restores synaptic plasticity and cognitive performance. These findings uncover a neurodevelopmental axis wherein neuronal SIRT6 deficiency dysregulates tryptophan metabolism to impair synaptic plasticity, identifying actionable targets for treating FGR-induced cognitive disorders.\n                  <\/jats:p>","DOI":"10.1038\/s12276-026-01739-7","type":"journal-article","created":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T10:07:07Z","timestamp":1781172427000},"page":"1987-2006","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting the SIRT6\u2013TDO2\/KYNA\u2013mTOR axis rescues synaptic and cognitive deficits in fetal growth restriction offspring"],"prefix":"10.1038","volume":"58","author":[{"given":"Shujuan","family":"Chang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nana","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianguo","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiuhong","family":"Kang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,11]]},"reference":[{"key":"1739_CR1","doi-asserted-by":"publisher","first-page":"755","DOI":"10.1016\/S2352-4642(18)30245-1","volume":"2","author":"C Gilchrist","year":"2018","unstructured":"Gilchrist, C., Cumberland, A., Walker, D. & Tolcos, M. 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