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Increasing evidence links deficiency or malfunctioning of the enzyme phosphoglycerate dehydrogenase (PHGDH), which converts 3\u2010phosphoglycerate to generate serine and the neurotransmitter glycine, with (drug\u2010resistant) epilepsy. Moreover, PHGDH, which is primarily expressed in astrocytes within the brain, has been identified as a critical enzyme in driving macrophage polarization toward an anti\u2010inflammatory state. Hence, PHGDH activators may be beneficial for treating DRE by exhibiting both antiseizure and anti\u2010inflammatory activity. The objective of this study was to identify such PHGDH activators.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We screened a drug repurposing library for PHGDH activators and assessed their antiseizure and anti\u2010inflammatory properties using various zebrafish and mouse epilepsy models and explored the mechanistic consequences of activating PHGDH in a cell line, in astrocytes, and in zebrafish heads. Finally, we assessed the efficacy of clioquinol as add\u2010on treatment in three severe DRE patients in a clinical open pilot proof\u2010of\u2010concept study.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We identified haloquinolines from a drug repurposing library as potent activators of PHGDH. The most promising haloquinoline clioquinol can increase the catalytic activity of PHGDH up to 2.5\u2010fold, thereby increasing de novo glycine biosynthesis and resulting in reduced glutamate levels. Moreover, we show that clioquinol has PHGDH\u2010dependent antiseizure activity as well as anti\u2010inflammatory properties in\u00a0vivo using various zebrafish and mouse epilepsy models. Finally, we demonstrate the efficacy of clioquinol as add\u2010on treatment in severe DRE patients; two patients showed a 37%\u201347% reduction in seizure frequency, and all three patients noted a positive impact on quality of life and seizure severity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance<\/jats:title>\n                    <jats:p>Increasing activity of PHGDH is a promising new approach to treat DRE.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/epi.18536","type":"journal-article","created":{"date-parts":[[2025,7,5]],"date-time":"2025-07-05T11:14:57Z","timestamp":1751714097000},"page":"3769-3784","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Clioquinol as a new therapy in epilepsy: From preclinical evidence to a proof\u2010of\u2010concept clinical 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