{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T11:10:33Z","timestamp":1788952233763,"version":"build-2803163510"},"reference-count":26,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"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>Doxorubicin (DOX) chemotherapy for hepatocellular carcinoma is hampered by tumor multidrug resistance and cumulative cardiotoxicity. Resveratrol (RES), a natural polyphenol with anti-tumor and antioxidant effects, may reverse DOX resistance and mitigate myocardial injury.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      To investigate whether RES reverses DOX resistance and boosts anti-tumor activity in HepG2-R\/SMMC-7721-R cells via apoptosis and EMT regulation, while protecting H9c2 cardiomyocytes; an H22 tumor-bearing mouse model was used to confirm the dual\n                      <jats:italic>in vivo<\/jats:italic>\n                      efficacy of combined RES + DOX therapy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      <jats:italic>In vitro<\/jats:italic>\n                      , CCK-8, morphology observation, wound-healing, Transwell and TUNEL assays detected cell proliferation, migration and apoptosis. Western blot measured apoptosis- and EMT-related proteins. Intracellular ROS, SOD and MDA were tested to clarify antioxidant cardioprotective mechanisms.\n                      <jats:italic>In vivo<\/jats:italic>\n                      , tumor volume, body weight, serum myocardial injury biomarkers (CK-MB, cTnI, BNP), oxidative-stress indicators, as well as H&amp;amp;E and Masson\u00b4s trichrome staining of myocardial tissue were detected to assess treatment efficacy and safety.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      DOX monotherapy barely inhibited resistant cell growth, while RES alone exerted weak anti-tumor activity; RES + DOX exerted obvious combined cytotoxicity to suppress proliferation, metastasis and induce tumor apoptosis. RES reversed EMT and enhanced the activation of Bax\/Bcl-2\/caspase-3 signaling. In H9c2 cells, RES eliminated DOX-triggered ROS overload, restored SOD, lowered MDA and suppressed cardiomyocyte apoptosis.\n                      <jats:italic>In vivo<\/jats:italic>\n                      , the combination achieved optimal tumor suppression, reversed DOX-induced weight loss, normalized serum cardiac-specific damage biomarkers and myocardial oxidative stress. Histological examinations demonstrated that RES alleviated DOX-provoked myocardial structural damage and interstitial fibrosis, and RES itself showed no intrinsic cardiac toxicity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>RES reverses DOX resistance and enhances anti-tumor effects; this finding is associated with the regulation of apoptosis and EMT signaling, and alleviates DOX-mediated cardiomyocyte oxidative injury through antioxidant pathways. This dual-action adjuvant strategy widens DOX\u00b4s therapeutic window for DOX-resistant hepatocellular carcinoma.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcell.2026.1925030","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T10:16:48Z","timestamp":1788949008000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Resveratrol reverses doxorubicin-resistance and alleviates doxorubicin-induced myocardial injury in hepatocellular carcinoma"],"prefix":"10.3389","volume":"14","author":[{"given":"Shiliang","family":"Diao","sequence":"first","affiliation":[{"name":"Special Consultation Clinic of General Internal Medicine, Jilin Provincial People\u2019s Hospital","place":["Changchun, Jilin Province, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiqi","family":"Diao","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Jilin Provincial Cancer Hospital","place":["Changchun, Jilin Province, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengmeng","family":"Wu","sequence":"additional","affiliation":[{"name":"Special Consultation Clinic of General Internal Medicine, Jilin Provincial People\u2019s Hospital","place":["Changchun, Jilin Province, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ningning","family":"Su","sequence":"additional","affiliation":[{"name":"Special Consultation Clinic of General Internal Medicine, Jilin Provincial People\u2019s Hospital","place":["Changchun, Jilin Province, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinji","family":"Quan","sequence":"additional","affiliation":[{"name":"Department of General Practice, Jilin Provincial People\u2019s Hospital","place":["Changchun, Jilin Province, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1016\/j.jconrel.2011.09.083","article-title":"Administration of resveratrol: what formulation solutions to bioavailability limitations?","volume":"158","author":"Amri","year":"2012","journal-title":"J. Control Release"},{"key":"B2","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1186\/s12935-021-01773-7","article-title":"Anti-tumor activity of resveratrol against gastric cancer: a review of recent advances with an emphasis on molecular pathways","volume":"21","author":"Ashrafizadeh","year":"2021","journal-title":"Cancer Cell Int."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1715","DOI":"10.3390\/cells10071715","article-title":"Hypoxia, metabolic reprogramming, and drug resistance in liver cancer","volume":"10","author":"Bao","year":"2021","journal-title":"Cells"},{"key":"B4","doi-asserted-by":"publisher","first-page":"19502","DOI":"10.1038\/s41598-022-23802-9","article-title":"Knockdown of the long noncoding RNA PURPL induces apoptosis and sensitizes liver cancer cells to doxorubicin","volume":"12","author":"Berhane","year":"2022","journal-title":"Sci. Rep."},{"key":"B5","doi-asserted-by":"publisher","first-page":"404","DOI":"10.1186\/s12951-023-02170-0","article-title":"Injectable hydrogel loaded with lysed OK-432 and doxorubicin for residual liver cancer after incomplete radiofrequency ablation","volume":"21","author":"Cao","year":"2023","journal-title":"J. Nanobiotechnol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"4435","DOI":"10.1016\/j.ymthe.2024.10.025","article-title":"N6-Methyladenosine modification activates the serine synthesis pathway to mediate therapeutic resistance in liver cancer","volume":"32","author":"Chan","year":"2024","journal-title":"Mol. Ther."},{"key":"B7","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1002\/iub.1749","article-title":"Effect of resveratrol on doxorubicin resistance in breast neoplasm cells by modulating PI3K\/Akt signaling pathway","volume":"70","author":"Chen","year":"2018","journal-title":"IUBMB Life"},{"key":"B8","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1038\/s41419-021-03614-x","article-title":"Regulated cell death pathways in doxorubicin-induced cardiotoxicity","volume":"12","author":"Christidi","year":"2021","journal-title":"Cell Death Dis."},{"key":"B9","doi-asserted-by":"publisher","first-page":"6037303","DOI":"10.1155\/2022\/6037303","article-title":"Resveratrol treats UVB-Induced photoaging by anti-MMP expression, through anti-inflammatory, antioxidant, and antiapoptotic properties, and treats photoaging by upregulating VEGF-B expression","volume":"2022","author":"Cui","year":"2022","journal-title":"Oxid. Med. Cell. Longev."},{"key":"B10","doi-asserted-by":"publisher","first-page":"1165","DOI":"10.1136\/gutjnl-2024-332125","article-title":"Immune checkpoint inhibitors and the liver: balancing therapeutic benefit and adverse events","volume":"74","author":"De Martin","year":"2025","journal-title":"Gut"},{"key":"B11","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1007\/s12032-025-02686-5","article-title":"The role of FOXA1 and miR-212-3p in molecular modulation of doxorubicin resistance in liver cancer","volume":"42","author":"Elfiky","year":"2025","journal-title":"Med. Oncol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"e110324","DOI":"10.15252\/embj.2021110324","article-title":"TFAM loss induces nuclear actin assembly upon mDia2 malonylation to promote liver cancer metastasis","volume":"41","author":"Huang","year":"2022","journal-title":"EMBO J."},{"key":"B14","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1007\/s12032-023-02181-9","article-title":"Synergistic induction of apoptosis in liver cancer cells: exploring the combined potential of doxorubicin and XL-888","volume":"40","author":"Kaplan","year":"2023","journal-title":"Med. Oncol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"115275","DOI":"10.1016\/j.biopha.2023.115275","article-title":"Resveratrol prevents ang II-induced cardiac hypertrophy by inhibition of NF-kappaB signaling","volume":"165","author":"Ma","year":"2023","journal-title":"Biomed. Pharmacother."},{"key":"B16","doi-asserted-by":"publisher","first-page":"113690","DOI":"10.1016\/j.ejmech.2021.113690","article-title":"Treatment for liver cancer: from sorafenib to natural products","volume":"224","author":"Man","year":"2021","journal-title":"Eur. J. Med. Chem."},{"key":"B17","doi-asserted-by":"publisher","first-page":"292","DOI":"10.1007\/s12012-022-09721-1","article-title":"Doxorubicin-induced cardiotoxicity: an overview on pre-clinical therapeutic approaches","volume":"22","author":"Sheibani","year":"2022","journal-title":"Cardiovasc. Toxicol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"B19","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1111\/aji.12489","article-title":"Resveratrol enhances apoptosis in endometriotic stromal cells","volume":"75","author":"Taguchi","year":"2016","journal-title":"Am. J. Reprod. Immunol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"4262","DOI":"10.1111\/bph.70085","article-title":"Dexrazoxane protects against doxorubicin-induced cardiotoxicity in susceptible human living myocardial slices: a proof-of-concept study","volume":"182","author":"van der Geest","year":"2025","journal-title":"Br. J. Pharmacol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"1669","DOI":"10.1007\/s12011-023-03758-1","article-title":"Resveratrol inhibits zinc deficiency-induced mitophagy and exerts cardiac cytoprotective effects","volume":"202","author":"Wang","year":"2024","journal-title":"Biol. Trace Elem. Res."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1429","DOI":"10.1007\/s10495-024-01995-w","article-title":"Resveratrol suppresses liver cancer progression by downregulating AKR1C3: targeting HCC with HSA nanomaterial as a carrier to enhance therapeutic efficacy","volume":"29","author":"Wang","year":"2024","journal-title":"Apoptosis"},{"key":"B23","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1016\/j.canlet.2017.02.007","article-title":"VCPA, a novel synthetic derivative of alpha-tocopheryl succinate, sensitizes human gastric cancer to doxorubicin-induced apoptosis via ROS-Dependent mitochondrial dysfunction","volume":"393","author":"Wu","year":"2017","journal-title":"Cancer Lett."},{"key":"B24","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1186\/s13046-016-0487-8","article-title":"Resveratrol reverses doxorubicin resistance by inhibiting epithelial-mesenchymal transition (EMT) through modulating PTEN\/akt signaling pathway in gastric cancer","volume":"36","author":"Xu","year":"2017","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"B25","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1186\/s43556-024-00184-0","article-title":"Signaling pathways in liver cancer: pathogenesis and targeted therapy","volume":"5","author":"Xue","year":"2024","journal-title":"Mol. Biomed."},{"key":"B26","doi-asserted-by":"publisher","first-page":"439","DOI":"10.1186\/s12951-025-03474-z","article-title":"Nanoscale engineered exosomes for dual delivery of Sirtuin3 and insulin to ignite mitochondrial recovery in myocardial ischemia-reperfusion","volume":"23","author":"Yang","year":"2025","journal-title":"J. Nanobiotechnol"},{"key":"B27","doi-asserted-by":"publisher","first-page":"116168","DOI":"10.1016\/j.bcp.2024.116168","article-title":"SIRT3 and SIRT4 double-genes remodeled the mitochondrial network to induce hepatocellular carcinoma cell line differentiation and suppress malignant phenotypes","volume":"223","author":"Zhang","year":"2024","journal-title":"Biochem. Pharmacol."}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2026.1925030\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T10:16:49Z","timestamp":1788949009000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2026.1925030\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,9]]},"references-count":26,"alternative-id":["10.3389\/fcell.2026.1925030"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2026.1925030","relation":{},"ISSN":["2296-634X"],"issn-type":[{"value":"2296-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,9]]},"article-number":"1925030"}}