{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T06:10:27Z","timestamp":1783923027744,"version":"3.55.0"},"reference-count":52,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T00:00:00Z","timestamp":1783900800000},"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>Objective<\/jats:title>\n                    <jats:p>\n                      Valproic acid (VPA) response in pediatric epilepsy shows high variability. This study investigated the association of tryptophan hydroxylase-2 (\n                      <jats:italic>TPH2<\/jats:italic>\n                      ) polymorphisms with VPA efficacy and adverse drug reactions (ADRs) in children.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      In a retrospective cohort of 199 children with epilepsy receiving VPA treatment,\n                      <jats:italic>TPH2<\/jats:italic>\n                      rs4570625 and rs1386494 were genotyped using Sequenom MassArray. Efficacy was categorized as uncontrolled seizure\n                      <jats:italic>vs.<\/jats:italic>\n                      seizure-free. ADRs were systemically recorded, and steady-state VPA concentrations were measured. Network pharmacology integrated protein-protein interactions, and functional enrichment to elucidate\n                      <jats:italic>TPH2<\/jats:italic>\n                      \u2019s role in VPA-related neurotoxicity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The rs4570625 polymorphism was significantly associated with VPA treatment outcomes. GG homozygotes exhibited higher seizure-free rates (\n                      <jats:italic>p<\/jats:italic>\n                      = 0.031) and lower incidence of neurological ADRs (\n                      <jats:italic>p<\/jats:italic>\n                      = 0.036). GG carriers also displayed significantly higher VPA serum concentrations. Network pharmacology analyses identified the serotonergic synapse as the dominant enriched pathway linking\n                      <jats:italic>TPH2<\/jats:italic>\n                      to VPA neurotoxicity, with\n                      <jats:italic>MAOA<\/jats:italic>\n                      and\n                      <jats:italic>SLC6A4<\/jats:italic>\n                      as key regulatory hubs. No significant associations were observed between rs1386494 polymorphism and VPA treatment outcomes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      <jats:italic>TPH2<\/jats:italic>\n                      rs4570625 may serve as a potential exploratory biomarker for predicting VPA efficacy and neurological toxicity in pediatric epilepsy, mediated through serotonergic pathway dysregulation. Genotype-guided personalization could optimize VPA therapy.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1821776","type":"journal-article","created":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T05:34:08Z","timestamp":1783920848000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Association of TPH2 polymorphisms with valproic acid efficacy and neurological adverse events in pediatric epilepsy"],"prefix":"10.3389","volume":"17","author":[{"given":"Jiahao","family":"Zhu","sequence":"first","affiliation":[{"name":"Department of Pharmacy, Shenzhen Baoan Women\u2019s and Children\u2019s Hospital","place":["Shenzhen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xixuan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Shenzhen Baoan Women\u2019s and Children\u2019s Hospital","place":["Shenzhen, China"]},{"name":"Department of Clinical Pharmacology, College of Pharmacy, Jinan University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianhuan","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Shenzhen Baoan Women\u2019s and Children\u2019s Hospital","place":["Shenzhen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanbing","family":"Xia","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Shenzhen Baoan Women\u2019s and Children\u2019s Hospital","place":["Shenzhen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaodong","family":"He","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology, College of Pharmacy, Jinan University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Shenzhen Baoan Women\u2019s and Children\u2019s Hospital","place":["Shenzhen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianping","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology, College of Pharmacy, Jinan University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaomei","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Shenzhen Baoan Women\u2019s and Children\u2019s Hospital","place":["Shenzhen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenzhou","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Shenzhen Baoan Women\u2019s and Children\u2019s Hospital","place":["Shenzhen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,13]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1542\/peds.2016-3908","article-title":"Incidence and prevalence of childhood epilepsy: a nationwide cohort study","volume":"139","author":"Aaberg","year":"2017","journal-title":"Pediatrics"},{"key":"B2","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1016\/j.lfs.2020.118826","article-title":"Revisiting the role of neurotransmitters in epilepsy: an updated review","volume":"265","author":"Akyuz","year":"2021","journal-title":"Life Sci."},{"key":"B3","doi-asserted-by":"publisher","first-page":"857","DOI":"10.1111\/j.1471-4159.2006.04277.x","article-title":"Serotonin and epilepsy","volume":"100","author":"Bagdy","year":"2007","journal-title":"J. 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