{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T04:10:24Z","timestamp":1793247024115,"version":"4.5.0"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T00:00:00Z","timestamp":1788134400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by loss of fragile X messenger ribonucleoprotein (FMRP) expression and characterized by synaptic dysfunction and cognitive impairment. However, the metabolic and epigenetic mechanisms underlying these abnormalities remain poorly understood. To address this gap, this study investigated the role of hexokinase 2 (HK2) in FXS pathogenesis and explored downstream metabolic and epigenetic mechanisms associated with synaptic dysfunction and cognitive impairment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Using an\n                      <jats:italic>Fmr1<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>\u2212\/Y<\/jats:italic>\n                      <\/jats:sup>\n                      mouse model, we evaluated HK2 expression and its cell-type specificity in hippocampal neurons. RNA immunoprecipitation (RIP) analysis was performed to examine the association between FMRP and\n                      <jats:italic>Hk2<\/jats:italic>\n                      mRNA. Genetic knockdown of HK2 was used to assess its effects on neurite outgrowth, synapse density, synaptic transmission, and hippocampal long-term potentiation (LTP). Finally, pharmacological experiments using the HDAC3 inhibitor RGFP966 were performed to examine whether modulation of H3K18la levels contributes to HK2-associated phenotypes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      HK2 expression was markedly elevated in hippocampal neurons\n                      <jats:italic>of Fmr1<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>\u2212\/Y<\/jats:italic>\n                      <\/jats:sup>\n                      mice. RIP analysis revealed an association between FMRP and\n                      <jats:italic>Hk2<\/jats:italic>\n                      mRNA, suggesting that HK2 may represent an FMRP-associated transcript. Genetic suppression of HK2 promoted neurite outgrowth, increased synapse density, and improved synaptic transmission and hippocampal long-term potentiation (LTP) in\n                      <jats:italic>Fmr1<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>\u2212\/Y<\/jats:italic>\n                      <\/jats:sup>\n                      mice. Mechanistically, HK2 knockdown selectively reduced H3K18la levels without affecting H3K18 acetylation, supporting a role for HK2 in regulating histone lactylation. Consistent with these findings, pharmacological inhibition of HDAC3 with RGFP966 increased H3K18la levels and attenuated the beneficial effects of HK2 suppression on neuronal morphology, synaptic plasticity, and cognitive function. Behavioral analyses demonstrated that modulation of the HK2-H3K18la axis improved spatial learning and memory in\n                      <jats:italic>Fmr1<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>\u2212\/Y<\/jats:italic>\n                      <\/jats:sup>\n                      mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Taken together, these findings support a role for the HK2-H3K18la axis in synaptic dysfunction in FXS. Targeting this metabolic-epigenetic axis may provide a potential avenue for future therapeutic exploration in FXS and related neurodevelopment disorders.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1903604","type":"journal-article","created":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T05:41:35Z","timestamp":1788154895000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["HK2 drives synaptic dysfunction in fragile X syndrome via epigenetic regulation of H3K18 lactylation"],"prefix":"10.3389","volume":"17","author":[{"given":"Yan","family":"Luan","sequence":"first","affiliation":[{"name":"Department of Pathology, Shaanxi Provincial People\u2019s Hospital","place":["Xi\u2019an, Shaanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanyue","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Neurobiology, Xi\u2019an Jiaotong University Health Science Center","place":["Xi\u2019an, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ningning","family":"Ma","sequence":"additional","affiliation":[{"name":"Xi\u2019an Medical University","place":["Xi\u2019an, Shaanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuming","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Shaanxi Provincial People\u2019s Hospital","place":["Xi\u2019an, Shaanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhao","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Shaanxi Provincial People\u2019s Hospital","place":["Xi\u2019an, Shaanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weihua","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Hematology, Shaanxi Provincial People\u2019s Hospital","place":["Xi\u2019an, Shaanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Hematology, Shaanxi Provincial People\u2019s Hospital","place":["Xi\u2019an, Shaanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingfei","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Hematology, Shaanxi Provincial People\u2019s Hospital","place":["Xi\u2019an, Shaanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,31]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"982","DOI":"10.3390\/cancers15030982","article-title":"Glucose metabolism reprogramming in bladder cancer: hexokinase 2 (HK2) as prognostic biomarker and target for bladder cancer therapy","volume":"15","author":"Afonso","year":"2023","journal-title":"Cancers"},{"key":"B2","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1016\/j.conb.2017.03.007","article-title":"Glucose metabolism in nerve terminals","volume":"45","author":"Ashrafi","year":"2017","journal-title":"Curr. 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