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L-2HG dehydrogenase (L2HGDH) deficiency, a rare autosomal recessive inborn error of metabolism associated with systemic L-2HG elevation, causes progressive neurological disability and increased brain tumor risk of unclear mechanism. Using an isogenic, patient-derived induced pluripotent stem cell system, we examined the impact of L2HGDH deficiency on neural progenitor cell (NPC) function and neuronal differentiation. L2HGDH deficiency caused L-2HG accumulation, NPC hyperproliferation, increased clonogenicity, and defective neuronal differentiation in 2D cultures and cortical spheroids. Editing the\n                    <jats:italic>L2HGDH<\/jats:italic>\n                    locus to WT reversed these effects. Inhibiting glutaminase reduced L-2HG levels and induced neuronal differentiation. L-2HG\u2013dependent inhibition of KDM5 histone demethylases led to widespread retention of H3K4me2\/3, markers of active gene expression, with prominent enrichment at the\n                    <jats:italic>MYC<\/jats:italic>\n                    locus and elevated\n                    <jats:italic>MYC<\/jats:italic>\n                    expression across multiple neural cell types. Despite broadly altered histone methylation, genetically or pharmacologically normalizing\n                    <jats:italic>MYC<\/jats:italic>\n                    completely restored neuronal differentiation. These data indicated that a primary metabolic disturbance activated\n                    <jats:italic>MYC<\/jats:italic>\n                    to favor self-renewal and suppress neuronal lineage commitment.\n                  <\/jats:p>","DOI":"10.1172\/jci197010","type":"journal-article","created":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T16:01:44Z","timestamp":1773763304000},"source":"Crossref","is-referenced-by-count":2,"title":["l-2-Hydroxyglutarate impairs neuronal differentiation through epigenetic activation of MYC expression"],"prefix":"10.1172","volume":"136","author":[{"given":"Wen","family":"Gu","sequence":"first","affiliation":[{"name":"Children\u2019s Medical Center Research Institute,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5172-0305","authenticated-orcid":true,"given":"Xun","family":"Wang","sequence":"additional","affiliation":[{"name":"Children\u2019s Medical Center Research 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