{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T22:39:14Z","timestamp":1771022354331,"version":"3.50.1"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T00:00:00Z","timestamp":1755820800000},"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. Chem."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Colorectal cancer (CRC) is a prevalent malignant tumor of the digestive tract. The FOLFOX regimen (oxaliplatin + calcium folinate + 5-fluorouracil) serves as the primary treatment for advanced CRC clinically, yet its application is significantly limited by substantial toxic side effects. Erianin, a natural compound from Chinese medicine <jats:italic>Dendrobium chrysotoxum<\/jats:italic> Lindl, demonstrates significant potential in both tumor growth inhibition and chemotherapy toxicity reduction. This study aims to investigate the potential of Erianin in reducing the toxicity of the FOLFOX regimen while enhancing its antitumor efficacy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This study integrated network toxicology and molecular docking to predict the potential targets of Erianin in alleviating FOLFOX-induced side effects. Using an orthotopic MC38 CRC transplantation model, we conducted a comprehensive evaluation of the effects of Erianin in mitigating FOLFOX-induced changes in body weight changes, hematological parameters, and histopathology of major organs (heart, liver, spleen, kidneys, and intestines). IHC analysis elucidated alterations in intestinal barrier proteins, AKT1\/mTOR pathway, and tumor proliferation and apoptosis biomarkers. Tumor progression was dynamically monitored by <jats:italic>in vivo<\/jats:italic> imaging.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The results showed that Erianin improved weight loss, pathological changes in organs, and reduction in peripheral blood cell counts (WBC, RBC, HGB, PLT, HCT) caused by FOLFOX in mice. Erianin reversed the inhibition of intestinal tight junction proteins (e.g. ZO-1, Occludin, Claudin-5) and AKT1\/mTOR pathway caused by FOLFOX. In addition, the tumor size was significantly reduced in the combination group, and the expression of the apoptosis marker Cleaved Caspase-3 was up-regulated, and the proliferation markers Ki67\/PCNA were down-regulated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>Erianin can enhance the anti-CRC effect of FOLFOX, and mitigates FOLFOX-induced toxicity by activating the AKT1\/mTOR pathway.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fchem.2025.1650197","type":"journal-article","created":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T09:35:59Z","timestamp":1755855359000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Natural product Erianin: mitigating FOLFOX toxicity and enhancing against colorectal cancer"],"prefix":"10.3389","volume":"13","author":[{"given":"Fuqin","family":"Yang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zeqiao","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haishan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mingxiao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhenwei","family":"He","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoqin","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yingru","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pei","family":"Long","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruirui","family":"Ding","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhengbin","family":"Lin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lijuan","family":"Deng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,8,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e447","DOI":"10.1016\/S1470-2045(14)70006-3","article-title":"Guidance on the management of diarrhoea during cancer chemotherapy","volume":"15","author":"Andreyev","year":"2014","journal-title":"Lancet Oncol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"4295","DOI":"10.1093\/nar\/gkae102","article-title":"Novel insights into the role of translesion synthesis polymerase in DNA incorporation and bypass of 5-fluorouracil in colorectal cancer","volume":"52","author":"Averill","year":"2024","journal-title":"Nucleic Acids Res."},{"key":"B3","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1038\/sj.bjc.6604134","article-title":"Cetuximab potentiates oxaliplatin cytotoxic effect through a defect in NER and DNA replication initiation","volume":"98","author":"Balin-Gauthier","year":"2008","journal-title":"Br. J. Cancer"},{"key":"B4","doi-asserted-by":"publisher","first-page":"154306","DOI":"10.1016\/j.phymed.2022.154306","article-title":"Role of curcumin in the treatment of acute kidney injury: research challenges and opportunities","volume":"104","author":"Cai","year":"2022","journal-title":"Phytomedicine"},{"key":"B5","doi-asserted-by":"publisher","first-page":"254","DOI":"10.1159\/000065474","article-title":"Combined irinotecan, oxaliplatin and 5-Fluorouracil in patients with advanced colorectal cancer","volume":"63","author":"Calvo","year":"2002","journal-title":"Oncology"},{"key":"B6","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1046\/j.1463-1318.5.s3.3.x","article-title":"Tournigand C. The evolving role of oxaliplatin in the management of colorectal cancer","volume":"3","author":"de Gramont","year":"2003","journal-title":"Colorectal Dis."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1467","DOI":"10.1016\/S0140-6736(19)32319-0","article-title":"Colorectal cancer","volume":"394","author":"Dekker","year":"2019","journal-title":"Lancet"},{"key":"B8","doi-asserted-by":"publisher","first-page":"521","DOI":"10.1186\/1471-2407-14-521","article-title":"Dose escalating study of cetuximab and 5-FU\/folinic acid (FA)\/oxaliplatin\/irinotecan (FOLFOXIRI) in first line therapy of patients with metastatic colorectal cancer","volume":"14","author":"Folprecht","year":"2014","journal-title":"BMC Cancer"},{"key":"B9","doi-asserted-by":"publisher","first-page":"890","DOI":"10.1007\/s00520-006-0040-y","article-title":"Cancer chemotherapy-induced diarrhoea and constipation: mechanisms of damage and prevention strategies","volume":"14","author":"Gibson","year":"2006","journal-title":"Support Care Cancer"},{"key":"B10","doi-asserted-by":"publisher","first-page":"669","DOI":"10.3390\/toxics11080669","article-title":"Inducing cytotoxicity in Colon cancer cells and suppressing cancer stem cells by dolasetron and ketoprofen through inhibition of RNA binding protein PUM1","volume":"11","author":"Gor","year":"2023","journal-title":"Toxics"},{"key":"B11","doi-asserted-by":"publisher","first-page":"744","DOI":"10.1111\/cas.14757","article-title":"5HT(3) RA plus dexamethasone plus aprepitant for controlling delayed chemotherapy-induced nausea and vomiting in colorectal cancer","volume":"112","author":"Hayashi","year":"2021","journal-title":"Cancer Sci."},{"key":"B12","first-page":"802","article-title":"Analysis of the risk factors for myelosuppression after chemoradiotherapy involving 5-fluorouracil and platinum for patients with esophageal cancer","volume":"58","author":"Kogo","year":"2011","journal-title":"Hepatogastroenterology"},{"key":"B13","doi-asserted-by":"publisher","first-page":"7069","DOI":"10.1158\/1078-0432.CCR-09-0688","article-title":"Phase I\/II trial of bevacizumab and radiotherapy for locally advanced inoperable colorectal cancer: vasculature-independent radiosensitizing effect of bevacizumab","volume":"15","author":"Koukourakis","year":"2009","journal-title":"Clin. Cancer Res."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1082","DOI":"10.3748\/wjg.v17.i8.1082","article-title":"Paclitaxel based vs oxaliplatin based regimens for advanced gastric cancer","volume":"17","author":"Li","year":"2011","journal-title":"World J. Gastroenterol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"154052","DOI":"10.1016\/j.phymed.2022.154052","article-title":"Huangqin decoction ameliorates DSS-Induced ulcerative colitis: role of gut microbiota and amino acid metabolism, mTOR pathway and intestinal epithelial barrier","volume":"100","author":"Li","year":"2022","journal-title":"Phytomedicine"},{"key":"B16","doi-asserted-by":"publisher","first-page":"144030","DOI":"10.1016\/j.foodchem.2025.144030","article-title":"Dual signal output detection of acetamiprid residues in medicine and food homology products via nanopore biosensor","volume":"481","author":"Li","year":"2025","journal-title":"Food Chem."},{"key":"B17","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1186\/s12935-024-03332-2","article-title":"Erianin inhibits the progression of triple-negative breast cancer by suppressing SRC-mediated cholesterol metabolism","volume":"24","author":"Li","year":"2024","journal-title":"Cancer Cell Int."},{"key":"B18","doi-asserted-by":"publisher","first-page":"643","DOI":"10.1007\/s11655-023-3558-7","article-title":"Chinese medicine combined with adjuvant chemotherapy for improving myelosuppression in colorectal cancer patients: a systematic review and network meta-analysis","volume":"30","author":"Li","year":"2024","journal-title":"Chin. J. Integr. Med."},{"key":"B19","doi-asserted-by":"publisher","first-page":"110247","DOI":"10.1016\/j.intimp.2023.110247","article-title":"Paeoniflorin promotes intestinal stem cell-mediated epithelial regeneration and repair via PI3K-AKT-mTOR signalling in ulcerative colitis","volume":"119","author":"Ma","year":"2023","journal-title":"Int. Immunopharmacol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"e261012","DOI":"10.1136\/bcr-2024-261012","article-title":"FOLFOX regimen induced severe hypokalaemia with hypocalcaemia and hypomagnesaemia","volume":"17","author":"Mahadevappa","year":"2024","journal-title":"BMJ Case Rep."},{"key":"B21","doi-asserted-by":"publisher","first-page":"522","DOI":"10.1038\/s41419-024-06902-4","article-title":"Erianin induces ferroptosis in GSCs via REST\/LRSAM1 mediated SLC40A1 ubiquitination to overcome TMZ resistance","volume":"15","author":"Mansuer","year":"2024","journal-title":"Cell Death Dis."},{"key":"B22","doi-asserted-by":"publisher","first-page":"475","DOI":"10.1093\/brain\/awac273","article-title":"TRPA1 modulation by Sigma-1 receptor prevents oxaliplatin-induced painful peripheral neuropathy","volume":"146","author":"Marcotti","year":"2023","journal-title":"Brain"},{"key":"B23","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1097\/SLA.0000000000005780","article-title":"Neoadjuvant chemotherapy with CAPOX versus chemoradiation for locally advanced rectal cancer with uninvolved mesorectal fascia (CONVERT): initial results of a phase III trial","volume":"277","author":"Mei","year":"2023","journal-title":"Ann. Surg."},{"key":"B24","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1016\/j.freeradbiomed.2023.05.008","article-title":"Erianin inhibits the growth and metastasis through autophagy-dependent ferroptosis in KRASG13D colorectal cancer","volume":"204","author":"Miao","year":"2023","journal-title":"Free Radic. Biol. Med."},{"key":"B25","doi-asserted-by":"publisher","first-page":"10316","DOI":"10.3748\/wjg.v20.i30.10316","article-title":"FOLFOX\/FOLFIRI pharmacogenetics: the call for a personalized approach in colorectal cancer therapy","volume":"20","author":"Mohelnikova-Duchonova","year":"2014","journal-title":"World J. Gastroenterol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"338","DOI":"10.1136\/gutjnl-2022-327736","article-title":"Global burden of colorectal cancer in 2020 and 2040: incidence and mortality estimates from GLOBOCAN","volume":"72","author":"Morgan","year":"2023","journal-title":"Gut"},{"key":"B27","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1002\/biof.1823","article-title":"The cardioprotective effects of nano-curcumin against doxorubicin-induced cardiotoxicity: a systematic review","volume":"48","author":"Moutabian","year":"2022","journal-title":"Biofactors"},{"key":"B28","doi-asserted-by":"publisher","first-page":"1416","DOI":"10.1046\/j.1365-2168.2002.02223.x","article-title":"Ranitidine as adjuvant treatment in colorectal cancer","volume":"89","author":"Nielsen","year":"2002","journal-title":"Br. J. Surg."},{"key":"B29","doi-asserted-by":"publisher","first-page":"115149","DOI":"10.1016\/j.ab.2023.115149","article-title":"Electrochemical detection of oxaliplatin induced DNA damage in G-quadruplex structures","volume":"671","author":"Osmano\u011fullar\u0131","year":"2023","journal-title":"Anal. Biochem."},{"key":"B30","doi-asserted-by":"publisher","first-page":"e157399","DOI":"10.1172\/JCI157399","article-title":"Targeting FAP\u03b1-expressing hepatic stellate cells overcomes resistance to antiangiogenics in colorectal cancer liver metastasis models","volume":"132","author":"Qi","year":"2022","journal-title":"J. Clin. Invest"},{"key":"B31","doi-asserted-by":"publisher","first-page":"1227","DOI":"10.1080\/0284186X.2016.1197420","article-title":"Oxaliplatin added to fluoropyrimidine for adjuvant treatment of colorectal cancer is associated with long-term impairment of peripheral nerve sensory function and quality of life","volume":"55","author":"Stefansson","year":"2016","journal-title":"Acta Oncol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1177\/1758834009355164","article-title":"Review: chemotherapy-Induced diarrhea: pathophysiology, frequency and guideline-based management","volume":"2","author":"Stein","year":"2010","journal-title":"Ther. Adv. Med. Oncol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1186\/s41065-024-00351-x","article-title":"Erianin inhibits the progression of DDP-resistant lung adenocarcinoma by regulating the Wnt\/\u03b2-catenin pathway and activating the caspase-3 for apoptosis in vitro and in vivo","volume":"161","author":"Tang","year":"2024","journal-title":"Hereditas"},{"key":"B34","doi-asserted-by":"publisher","first-page":"1027","DOI":"10.1177\/1534735418794885","article-title":"Adjunctive treatments for the prevention of Chemotherapy- and radiotherapy-induced mucositis","volume":"17","author":"Thomsen","year":"2018","journal-title":"Integr. Cancer Ther."},{"key":"B35","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1159\/000336902","article-title":"Results of adjuvant FOLFOX regimens in stage III colorectal cancer patients: retrospective analysis of 667 patients","volume":"84","author":"Uncu","year":"2013","journal-title":"Oncology"},{"key":"B36","doi-asserted-by":"publisher","first-page":"109570","DOI":"10.1016\/j.biopha.2019.109570","article-title":"Antitumor effects of immunity-enhancing traditional Chinese medicine","volume":"121","author":"Wang","year":"2020","journal-title":"Biomed. Pharmacother."},{"key":"B37","doi-asserted-by":"publisher","first-page":"1159","DOI":"10.1016\/S1470-2045(17)30457-6","article-title":"First-line selective internal radiotherapy plus chemotherapy versus chemotherapy alone in patients with liver metastases from colorectal cancer (FOXFIRE, SIRFLOX, and FOXFIRE-global): a combined analysis of three multicentre, randomised, phase 3 trials","volume":"18","author":"Wasan","year":"2017","journal-title":"Lancet Oncol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"7973","DOI":"10.3390\/ijms25147973","article-title":"Discovery of the natural bibenzyl compound erianin in dendrobium inhibiting the growth and EMT of gastric cancer through downregulating the LKB1-SIK2\/3-PARD3 pathway","volume":"25","author":"Wei","year":"2024","journal-title":"Int. J. Mol. Sci."},{"key":"B39","doi-asserted-by":"publisher","first-page":"775506","DOI":"10.3389\/fphar.2021.775506","article-title":"Natural product erianin inhibits bladder cancer cell growth by inducing ferroptosis via NRF2 inactivation","volume":"12","author":"Xiang","year":"2021","journal-title":"Front. Pharmacol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"1534","DOI":"10.3389\/fphar.2018.01534","article-title":"A review of resveratrol as a potent chemoprotective and synergistic agent in cancer chemotherapy","volume":"2019","author":"Xiao","year":"2019","journal-title":"Front. Pharmacol."},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1042\/BSR20210093","article-title":"Erianin induces triple-negative breast cancer cells apoptosis by activating PI3K\/Akt pathway","volume":"41","author":"Xu","year":"2021","journal-title":"Biosci. Rep."},{"key":"B42","doi-asserted-by":"publisher","first-page":"609705","DOI":"10.3389\/fimmu.2020.609705","article-title":"Research status and molecular mechanism of the traditional Chinese medicine and antitumor therapy combined strategy based on tumor microenvironment","volume":"11","author":"Zhang","year":"2020","journal-title":"Front. Immunol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"4511","DOI":"10.1002\/ptr.7154","article-title":"Erianin inhibits human lung cancer cell growth via PI3K\/Akt\/mTOR pathway in vitro and in vivo","volume":"35","author":"Zhang","year":"2021","journal-title":"Phytother. Res."},{"key":"B44","doi-asserted-by":"publisher","first-page":"2115","DOI":"10.7150\/thno.69424","article-title":"Platinum-based drugs for cancer therapy and anti-tumor strategies","volume":"12","author":"Zhang","year":"2022","journal-title":"Theranostics"},{"key":"B45","doi-asserted-by":"publisher","first-page":"14870","DOI":"10.1021\/acs.jafc.3c04154","article-title":"Chemical constituents, bioactivities, and pharmacological mechanisms of dendrobium officinale: a review of the past decade","volume":"71","author":"Zhang","year":"2023","journal-title":"J. Agric. Food Chem."},{"key":"B46","doi-asserted-by":"publisher","first-page":"156970","DOI":"10.1016\/j.phymed.2025.156970","article-title":"Mulberry leaf improves type 2 diabetes in mice via gut microbiota-SCFAs-GPRs axis and AMPK signaling pathway","volume":"145","author":"Zhang","year":"2025","journal-title":"Phytomedicine"},{"key":"B47","doi-asserted-by":"publisher","first-page":"117046","DOI":"10.1016\/j.bcp.2025.117046","article-title":"Erianin inhibits the proliferation and stemness of pancreatic cancer cells by interacting with MEK1\/2","volume":"239","author":"Zhu","year":"2025","journal-title":"Biochem. Pharmacol."}],"container-title":["Frontiers in Chemistry"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fchem.2025.1650197\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T09:36:00Z","timestamp":1755855360000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fchem.2025.1650197\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,22]]},"references-count":47,"alternative-id":["10.3389\/fchem.2025.1650197"],"URL":"https:\/\/doi.org\/10.3389\/fchem.2025.1650197","relation":{},"ISSN":["2296-2646"],"issn-type":[{"value":"2296-2646","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,22]]},"article-number":"1650197"}}