{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T06:01:45Z","timestamp":1785132105393,"version":"3.55.0"},"reference-count":31,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T00:00:00Z","timestamp":1785110400000},"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. Cell Dev. Biol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Glioma is an aggressive malignant brain tumor with poor prognosis. Resveratrol (RES) possesses anti-tumor activity yet limited clinical value. Valproic acid (VPA), a histone deacetylase inhibitor, boosts multiple anti-cancer drugs\u2019 efficacy. This study explored RES\/VPA synergy in glioma cell lines and syngeneic mouse tumors, and confirmed the reactive oxygen species (ROS)-programmed cell death protein 4 (PDCD4)-Bax cascade drives combined pro-apoptotic and anti-invasive effects.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      CCK-8 detected cell proliferation; morphology and AO\/EB staining assessed apoptosis. Wound healing and transwell assays measured migration. Western blot analyzed apoptosis and migration-related proteins, including PDCD4. Dihydroethidium staining tested intracellular ROS. Rescue assays used N-acetylcysteine (NAC) and PDCD4 knockdown; subcutaneous syngeneic mice validated\n                      <jats:italic>in vivo<\/jats:italic>\n                      anti-tumor activity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      VPA alone exerted no significant cytotoxicity on glioma cells (p &amp;gt; 0.05 vs. NC), while RES inhibited U87MG and U251 cell proliferation in a concentration-dependent manner (p &amp;lt; 0.05, p &amp;lt; 0.01 vs. NC). RES\/VPA co-treatment significantly enhanced cytotoxicity, suppressed migration and induced glioma cell apoptosis, with anti-tumor efficacy comparable to clinical doxorubicin (p &amp;gt; 0.05 Com vs. DOX; p &amp;lt; 0.01 Com vs. RES). Mechanistically, the combination markedly increased intracellular ROS accumulation (p &amp;lt; 0.001 Com vs. RES), upregulated PDCD4 expression (p &amp;lt; 0.01 Com vs. RES), and modulated apoptosis- and EMT-related protein levels to trigger cell apoptosis. NAC-mediated ROS scavenging or PDCD4 knockdown significantly abolished the synergistic pro-apoptotic effect of the combination therapy (p &amp;lt; 0.01 vs. Com), verifying the critical ROS-PDCD4 signaling function.\n                      <jats:italic>In vivo<\/jats:italic>\n                      , RES\/VPA co-treatment significantly inhibited tumor growth (p &amp;lt; 0.01 Com vs. RES), and low-dose combination achieved equivalent efficacy to high-dose RES monotherapy (p &amp;gt; 0.05) without obvious toxic effects.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>RES combined with VPA exerts synergistic anti-glioma effects via the ROS-PDCD4-Bax signaling pathway, providing experimental evidence for VPA as an adjuvant in RES-based therapy. This combinatorial strategy overcomes the insufficient anti-tumor potency of RES monotherapy at the cellular and murine tumor level, expands the preclinical antitumor research value of natural polyphenols, and provides laboratory experimental reference for subsequent translational exploration of glioma therapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcell.2026.1886066","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T05:40:39Z","timestamp":1785130839000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Valproic acid sensitizes resveratrol to induce glioma cell apoptosis via the ROS-PDCD4-Bax signaling axis"],"prefix":"10.3389","volume":"14","author":[{"given":"He","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Neurology, Jilin Provincial People\u2019s Hospital","place":["Changchun, Jilin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xunjuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Jilin Provincial People\u2019s Hospital","place":["Changchun, Jilin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Li","sequence":"additional","affiliation":[{"name":"Neurobiology Laboratory, Wannan Medical College","place":["Wuhu, Anhui, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,27]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"579","DOI":"10.1186\/s12935-021-02280-5","article-title":"Resveratrol mediates its anti-cancer effects by Nrf2 signaling pathway activation","volume":"21","author":"Alavi","year":"2021","journal-title":"Cancer Cell Int."},{"key":"B2","doi-asserted-by":"publisher","first-page":"188","DOI":"10.3390\/cancers13020188","article-title":"Resveratrol's anti-cancer effects through the modulation of tumor glucose metabolism","volume":"13","author":"Brockmueller","year":"2021","journal-title":"Cancers"},{"key":"B3","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1016\/j.annpat.2016.12.001","article-title":"Immunotherapy in brain tumors","volume":"37","author":"De Carli","year":"2017","journal-title":"Ann. Pathol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"581","DOI":"10.1186\/s12885-018-4504-5","article-title":"Resveratrol induces autophagy-dependent apoptosis in HL-60 cells","volume":"18","author":"Fan","year":"2018","journal-title":"BMC Cancer"},{"key":"B5","doi-asserted-by":"publisher","first-page":"14224","DOI":"10.3390\/ijms232214224","article-title":"Glioma stem cells: novel data obtained by single-cell sequencing","volume":"23","author":"Gisina","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1145","DOI":"10.1016\/j.etp.2013.05.006","article-title":"Induction of miR-21-PDCD4 signaling by UVB in JB6 cells involves ROS-mediated MAPK pathways","volume":"65","author":"Hou","year":"2013","journal-title":"Exp. Toxicol. Pathol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"759","DOI":"10.1038\/s41401-021-00679-4","article-title":"Role of TRPM2 in brain tumours and potential as a drug target","volume":"43","author":"Ji","year":"2022","journal-title":"Acta Pharmacol. Sin."},{"key":"B8","doi-asserted-by":"publisher","first-page":"876","DOI":"10.1038\/s42256-024-00868-w","article-title":"A transformer-based weakly supervised computational pathology method for clinical-grade diagnosis and molecular marker discovery of gliomas","volume":"6","author":"Jiang","year":"2024","journal-title":"Nat. Mach. Intell."},{"key":"B9","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/j.pediatrneurol.2019.04.019","article-title":"Valproic acid-induced coagulopathy","volume":"98","author":"Kumar","year":"2019","journal-title":"Pediatr. Neurol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1007\/s11060-017-2499-4","article-title":"CD147 and glioma: a meta-analysis","volume":"134","author":"Li","year":"2017","journal-title":"J. Neurooncol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1186\/s13578-019-0312-0","article-title":"Combination chemotherapy of valproic acid (VPA) and gemcitabine regulates STAT3\/Bmi1 pathway to differentially potentiate the motility of pancreatic cancer cells","volume":"9","author":"Li","year":"2019","journal-title":"Cell Biosci."},{"key":"B12","doi-asserted-by":"publisher","first-page":"e70213","DOI":"10.1002\/prp2.70213","article-title":"Paeonol inhibits cell growth by inducing ferroptosis in human glioma cells","volume":"14","author":"Li","year":"2026","journal-title":"Pharmacol. Res. Perspect."},{"key":"B13","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1080\/10717544.2021.2023700","article-title":"GSH-responsive poly-resveratrol based nanoparticles for effective drug delivery and reversing multidrug resistance","volume":"29","author":"Liping","year":"2022","journal-title":"Drug Deliv."},{"key":"B14","doi-asserted-by":"publisher","first-page":"109395","DOI":"10.1016\/j.cbi.2021.109395","article-title":"Resveratrol inhibits matrix metalloproteinase-1 and -3 expression by suppressing of p300\/NFkappaB acetylation in TNF-alpha-treated human dermal fibroblasts","volume":"337","author":"Lu","year":"2021","journal-title":"Chem. Biol. Interact."},{"key":"B15","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1007\/s00441-020-03187-9","article-title":"CiRS-126 inhibits proliferation of ovarian granulosa cells through targeting the miR-21-PDCD4-ROS axis in a polycystic ovarian syndrome model","volume":"381","author":"Lu","year":"2020","journal-title":"Cell Tissue Res."},{"key":"B16","doi-asserted-by":"publisher","first-page":"16597","DOI":"10.3390\/ijms242316597","article-title":"Therapeutic potential of resveratrol for glioma: a systematic review and meta-analysis of animal model studies","volume":"24","author":"Lu\u00eds","year":"2023","journal-title":"Int. J. Mol. Sci."},{"key":"B17","doi-asserted-by":"publisher","first-page":"102819","DOI":"10.1016\/j.ctim.2022.102819","article-title":"Role of resveratrol supplementation in regulation of glucose hemostasis, inflammation and oxidative stress in patients with diabetes mellitus type 2: a randomized, placebo-controlled trial","volume":"66","author":"Mahjabeen","year":"2022","journal-title":"Complement. Ther. Med."},{"key":"B18","doi-asserted-by":"publisher","first-page":"588","DOI":"10.11477\/mf.1436204432","article-title":"Chemotherapy for glioma","volume":"49","author":"Saito","year":"2021","journal-title":"No Shinkei Geka"},{"key":"B19","doi-asserted-by":"publisher","first-page":"1132","DOI":"10.1007\/s12010-017-2684-0","article-title":"Valproic acid promotes apoptosis and cisplatin sensitivity through downregulation of H19 noncoding RNA in ovarian A2780 cells","volume":"185","author":"Sajadpoor","year":"2018","journal-title":"Appl. Biochem. Biotechnol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"115346","DOI":"10.1016\/j.jpba.2023.115346","article-title":"Resveratrol improves the cytotoxic effect of CD8+ T cells in the tumor microenvironment by regulating HMMR\/Ferroptosis in lung squamous cell carcinoma","volume":"229","author":"Shan","year":"2023","journal-title":"J. Pharm. Biomed. Anal."},{"key":"B21","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1002\/ptr.8379","article-title":"Resveratrol bioavailability after oral administration: a meta-analysis of clinical trial data","volume":"39","author":"Szymkowiak","year":"2025","journal-title":"Phytother. Res."},{"key":"B22","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1007\/s13205-025-04691-x","article-title":"Mitochondria-mediated pyroptosis: anti-glioblastoma mechanism of the frankincense-derived compound \u03b2-boswellic acid","volume":"16","author":"Tang","year":"2026","journal-title":"3 Biotech."},{"key":"B23","doi-asserted-by":"publisher","first-page":"476","DOI":"10.11477\/mf.1436204419","article-title":"Glioma cell biology","volume":"49","author":"Tateishi","year":"2021","journal-title":"No Shinkei Geka"},{"key":"B24","doi-asserted-by":"publisher","first-page":"155636","DOI":"10.1016\/j.prp.2024.155636","article-title":"Recent update on anti-tumor mechanisms of valproic acid in glioblastoma multiforme","volume":"263","author":"Vatankhah","year":"2024","journal-title":"Pathol. Res. Pract."},{"key":"B25","doi-asserted-by":"publisher","first-page":"731","DOI":"10.3390\/toxins11120731","article-title":"The cytotoxicity effect of resveratrol: cell cycle arrest and induced apoptosis of breast cancer 4T1 cells","volume":"11","author":"Wu","year":"2019","journal-title":"Toxins"},{"key":"B26","doi-asserted-by":"publisher","first-page":"107198","DOI":"10.1016\/j.burns.2024.07.002","article-title":"Resveratrol promotes diabetic wound healing by inhibiting ferroptosis in vascular endothelial cells","volume":"50","author":"Xiao","year":"2024","journal-title":"Burns"},{"key":"B27","doi-asserted-by":"publisher","first-page":"3673","DOI":"10.1038\/s41467-023-39401-9","article-title":"SLC7A11 expression level dictates differential responses to oxidative stress in cancer cells","volume":"14","author":"Yan","year":"2023","journal-title":"Nat. Commun."},{"key":"B28","doi-asserted-by":"publisher","first-page":"810572","DOI":"10.3389\/fimmu.2022.810572","article-title":"A novel inflammation-related lncRNAs prognostic signature identifies LINC00346 in promoting proliferation, migration, and immune infiltration of glioma","volume":"13","author":"Zeng","year":"2022","journal-title":"Front. Immunol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"110160","DOI":"10.1016\/j.ecoenv.2019.110160","article-title":"ROS-mediated miR-21-5p regulates the proliferation and apoptosis of Cr(VI)-exposed L02 hepatocytes via targeting PDCD4","volume":"191","author":"Zhang","year":"2020","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"B30","doi-asserted-by":"publisher","first-page":"301","DOI":"10.33549\/physiolres.935007","article-title":"Double-edged sword effect of reactive oxygen species (ROS) in tumor development and carcinogenesis","volume":"72","author":"Zhao","year":"2023","journal-title":"Physiol. Res."},{"key":"B31","doi-asserted-by":"publisher","first-page":"3177","DOI":"10.1080\/21655979.2021.1946358","article-title":"MicroRNA-183-5p protects human derived cell line SH-SY5Y cells from mepivacaine-induced injury","volume":"12","author":"Zhou","year":"2021","journal-title":"Bioengineered"}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2026.1886066\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T05:40:40Z","timestamp":1785130840000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2026.1886066\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,27]]},"references-count":31,"alternative-id":["10.3389\/fcell.2026.1886066"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2026.1886066","relation":{},"ISSN":["2296-634X"],"issn-type":[{"value":"2296-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,27]]},"article-number":"1886066"}}