{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T10:04:15Z","timestamp":1789380255595,"version":"build-2803163510"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T00:00:00Z","timestamp":1789344000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004479","name":"Natural Science Foundation of Jiangxi Province","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004479","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Burkitt lymphoma (BL) has limited therapies and poor prognosis in elderly or relapsed patients. Valproic acid (VPA) exhibits broad anti-tumor activity, but its quantitative efficacy and molecular mechanism in EBV-positive BL remain undefined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      VPA activity in Daudi, Raji, Namalwa BL cell lines (n = 3 biological replicates per assay) was assessed using CCK-8 viability (24\u00a0h\/48\u00a0h IC\n                      <jats:sub>50<\/jats:sub>\n                      values), EdU proliferation, PI cell-cycle, and Annexin V\/PI dual-staining apoptosis assays.\n                      <jats:italic>In vivo<\/jats:italic>\n                      efficacy was tested in Namalwa CDX (control n = 5, VPA n = 6) and three independent EBV-positive PDX models (6 mice\/group for each PDX line), with daily 400\u00a0mg\/kg intraperitoneal VPA administration for 1\u20133\u00a0weeks;\n                      <jats:italic>ex vivo<\/jats:italic>\n                      drug response of PDX fragments was quantified via hydrogel embedded histoculture drug sensitivity test (HDST). RNA-seq was conducted on PDX No.1 tumor tissues (VPA vs. saline control, n = 3 per group). PFN2 and PI3K\/AKT pathway alterations were validated by RT-qPCR, Western blot, PFN2 knockdown\/overexpression, and PI3K\/AKT inhibitor combination assays.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      24\u00a0h IC\n                      <jats:sub>50<\/jats:sub>\n                      values of VPA were 20.15, 4.672, 7.769\u00a0mM for Daudi, Raji, Namalwa, while 48\u00a0h IC\n                      <jats:sub>50<\/jats:sub>\n                      decreased to 4.891, 2.283, 0.4836\u00a0mM. At 2\u00a0mM VPA treatment for 24\u00a0h, total apoptosis rates increased by 14.22% (Daudi), 10.20% (Raji), and 18.68% (Namalwa). VPA induced G0\/G1 cell-cycle arrest across all 3\u00a0cell lines. In CDX and three PDX models, VPA treatment reduced tumor weight (CDX: control 1.132\u00a0g vs. VPA 0.365\u00a0g,\n                      <jats:italic>p<\/jats:italic>\n                      = 0.0207, No.1: control 1.450\u00a0g vs. VPA 1.013\u00a0g,\n                      <jats:italic>p<\/jats:italic>\n                      = 0.049, No.2: control 1.283\u00a0g vs. VPA 0.913\u00a0g,\n                      <jats:italic>p<\/jats:italic>\n                      = 0.0295, No.3: control 1.371\u00a0g vs. VPA 0.9239,\n                      <jats:italic>p<\/jats:italic>\n                      = 0.0062) without body weight loss. RNA-seq analysis identified PFN2 as an exploratory candidate transcript with nominal transcriptional downregulation upon VPA administration (log\n                      <jats:sub>2<\/jats:sub>\n                      FC = \u22120.3213, raw p = 0.0355, FDR = 0.6149), and KEGG enrichment revealed perturbation of the PI3K\/AKT signaling pathway. VPA reduced PFN2 mRNA and protein abundance\n                      <jats:italic>in vitro<\/jats:italic>\n                      and\n                      <jats:italic>in vivo<\/jats:italic>\n                      . PFN2 knockdown recapitulated proliferation suppression and reduced p-PI3K\/p-AKT levels; PFN2 overexpression partially restored cell proliferation and PI3K\/AKT phosphorylation, which could be attenuated by VPA treatment. Co-administration of VPA with idelalisib or capivasertib produced stronger anti-proliferative effects of BL.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      VPA exerts potent anti-tumor activity against EBV-positive BL\n                      <jats:italic>in vitro<\/jats:italic>\n                      and in multiple xenograft models, associated with PFN2 downregulation and suppressed PI3K\/AKT signaling.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1925552","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T09:23:18Z","timestamp":1789377798000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Anti-tumor activity of valproic acid in EBV-positive Burkitt lymphoma via PFN2-associated PI3K\/AKT pathway repression"],"prefix":"10.3389","volume":"17","author":[{"given":"Yongliang","family":"Zheng","sequence":"first","affiliation":[{"name":"Department of Hematology, The Second Affiliated Hospital of Xi\u2019an Jiaotong University","place":["Xi\u2019an, Shaanxi, China"]},{"name":"Department of Hematology, The Affiliated Hospital of Jinggangshan University","place":["Ji\u2019an, Jiangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxiu","family":"Yang","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Jiangxi Science and Technology Normal University","place":["Nanchang, Jiangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shouhua","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of General Surgery, Jiangxi Provincial Children\u2019s Hospital, The Affiliated Children\u2019s Hospital of Nanchang Medical College","place":["Nanchang, Jiangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Hematology, The Second Affiliated Hospital of Xi\u2019an Jiaotong University","place":["Xi\u2019an, Shaanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zujie","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Hematology, The Second Affiliated Hospital of Xi\u2019an Jiaotong University","place":["Xi\u2019an, Shaanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanqiao","family":"He","sequence":"additional","affiliation":[{"name":"Center of Laboratory Animal Science, Nanchang University","place":["Nanchang, Jiangxi, China"]},{"name":"Key Laboratory of New Drug Evaluation and Transformation of Jiangxi Province","place":["Nanchang, Jiangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaoling","family":"Luo","sequence":"additional","affiliation":[{"name":"Clinical Medicine Research Center, First Affiliated Hospital of Gannan Medical University","place":["Ganzhou, Jiangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aili","family":"He","sequence":"additional","affiliation":[{"name":"Department of Hematology, The Second Affiliated Hospital of Xi\u2019an Jiaotong University","place":["Xi\u2019an, Shaanxi, China"]},{"name":"National-Local Joint Engineering Research Center of Biodiagnostics & Biotherapy, The Second Affiliated Hospital of Xi\u2019an Jiaotong University","place":["Xi\u2019an, Shaanxi, China"]},{"name":"Department of Tumor and Immunology, Precision Medical Institute, Xi\u2019an Jiaotong University","place":["Xi\u2019an, Shaanxi, China"]},{"name":"Xi\u2019an Key Laboratory of Hematological Diseases","place":["Xi\u2019an, Shaanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1186\/s12967-022-03405-8","article-title":"Patient-derived xenograft (PDX) models, applications and challenges in cancer research","volume":"20","author":"Abdolahi","year":"2022","journal-title":"J. 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