{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T14:55:44Z","timestamp":1777560944364,"version":"3.51.4"},"reference-count":41,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T00:00:00Z","timestamp":1774224000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82473439"],"award-info":[{"award-number":["82473439"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82272705"],"award-info":[{"award-number":["82272705"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82503486"],"award-info":[{"award-number":["82503486"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Shanghai &quot;Rising Stars of Medical Talents&quot; Youth Development Program of the Shanghai Mu-nicipal Health Commission","award":["2024-70"],"award-info":[{"award-number":["2024-70"]}]},{"name":"Naval Medical University &quot;Deep Blue&quot; Project Talent Program, the First Affiliated Hospital of Naval Medical University Special Project for Basic Medical Research","award":["2023QD003"],"award-info":[{"award-number":["2023QD003"]}]},{"name":"Naval Medical University &quot;Deep Blue&quot; Project Talent Program, the First Affiliated Hospital of Naval Medical University Special Project for Basic Medical Research","award":["2023PY04"],"award-info":[{"award-number":["2023PY04"]}]},{"name":"the First Affiliated Hospital of Naval Medical University Special Project for Clinical Research","award":["2024LYA02"],"award-info":[{"award-number":["2024LYA02"]}]},{"name":"the first batch of open research projects of Shanghai Key Laboratories","award":["2025QN02"],"award-info":[{"award-number":["2025QN02"]}]},{"name":"the first batch of open research projects of Shanghai Key Laboratories","award":["2025QN12"],"award-info":[{"award-number":["2025QN12"]}]},{"name":"Naval Medical University Project","award":["2024QN028"],"award-info":[{"award-number":["2024QN028"]}]},{"name":"Shanghai Shenkang Hospital Development Center, Shanghai Clinical Cohort Project","award":["SHDC2025CCS019"],"award-info":[{"award-number":["SHDC2025CCS019"]}]},{"name":"Shanghai Science and Technology Plan Project","award":["25SF1901500"],"award-info":[{"award-number":["25SF1901500"]}]},{"name":"Major National Science and Technology Project","award":["2023ZD0500103"],"award-info":[{"award-number":["2023ZD0500103"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>5-Fluorouracil (5-Fu) remains essential in colorectal cancer (CRC) treatment, but monotherapy causes severe toxicity and faces chemoresistance. Combination regimens are encouraged to improve efficacy and safety. Natural compounds like Baicalin show anti-tumor potential in other gastrointestinal cancers, yet their role in CRC, particularly in overcoming 5-Fu resistance, is underexplored. The combined effect of Baicalin and 5-Fu was evaluated through in vitro functional assays and an in vivo xenograft model. Mechanisms were investigated using Western blot, qPCR, and RNA-seq. Baicalin enhanced 5-Fu to inhibit CRC progression both in vitro and in vivo. Mechanistically, Baicalin enhanced 5-Fu cytotoxicity by activating the MLKL-dependent necroptosis pathway. This study proposes the Baicalin and 5-Fu combination as a novel and potent chemosensitizing strategy for CRC, especially in 5-Fu-resistant cases, and provides a mechanistic rationale for Baicalin as a chemotherapy-enhancing agent.<\/jats:p>","DOI":"10.3390\/ijms27062919","type":"journal-article","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T16:40:20Z","timestamp":1774284020000},"page":"2919","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Baicalin Augments 5-Fluorouracil Efficacy in Colorectal Cancer by Triggering MLKL-Dependent Necroptosis: A Novel Strategy to Overcome Chemoresistance"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9554-0592","authenticated-orcid":false,"given":"Jingwen","family":"Yuan","sequence":"first","affiliation":[{"name":"Colorectal Surgery Department, Changhai Hospital, Naval Medical University, Shanghai 200433, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhiying","family":"Peng","sequence":"additional","affiliation":[{"name":"Colorectal Surgery Department, Changhai Hospital, Naval Medical University, Shanghai 200433, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rongbo","family":"Wen","sequence":"additional","affiliation":[{"name":"Colorectal Surgery Department, Changhai Hospital, Naval Medical University, Shanghai 200433, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leqi","family":"Zhou","sequence":"additional","affiliation":[{"name":"Colorectal Surgery Department, Changhai Hospital, Naval Medical University, Shanghai 200433, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fuao","family":"Cao","sequence":"additional","affiliation":[{"name":"Colorectal Surgery Department, Changhai Hospital, Naval Medical University, Shanghai 200433, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tianshuai","family":"Zhang","sequence":"additional","affiliation":[{"name":"Colorectal Surgery Department, Changhai Hospital, Naval Medical University, Shanghai 200433, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yingjie","family":"Wu","sequence":"additional","affiliation":[{"name":"Colorectal Surgery Department, Changhai Hospital, Naval Medical University, Shanghai 200433, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiayue","family":"Wu","sequence":"additional","affiliation":[{"name":"Colorectal Surgery Department, Changhai Hospital, Naval Medical University, Shanghai 200433, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ran","family":"Lin","sequence":"additional","affiliation":[{"name":"Colorectal Surgery Department, Changhai Hospital, Naval Medical University, Shanghai 200433, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5416-3559","authenticated-orcid":false,"given":"Guanyu","family":"Yu","sequence":"additional","affiliation":[{"name":"Colorectal Surgery Department, Changhai Hospital, Naval Medical University, Shanghai 200433, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3094-9711","authenticated-orcid":false,"given":"Wei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Colorectal Surgery Department, Changhai Hospital, Naval Medical University, Shanghai 200433, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,23]]},"reference":[{"key":"ref_1","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA A Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1001\/jama.2021.0106","article-title":"Diagnosis and Treatment of Metastatic Colorectal Cancer: A Review","volume":"325","author":"Biller","year":"2021","journal-title":"JAMA"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1200\/JCO.22.01690","article-title":"Treatment of Metastatic Colorectal Cancer: ASCO Guideline","volume":"41","author":"Morris","year":"2022","journal-title":"J. Clin. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1016\/j.tips.2023.01.003","article-title":"Metastatic colorectal cancer: Mechanisms and emerging therapeutics","volume":"44","author":"Shin","year":"2023","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"107447","DOI":"10.1016\/j.pharmthera.2019.107447","article-title":"5-fluorouracil and other fluoropyrimidines in colorectal cancer: Past, present and future","volume":"206","author":"Vodenkova","year":"2019","journal-title":"Pharmacol. Ther."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1291","DOI":"10.1016\/j.annonc.2020.06.022","article-title":"Localised colon cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up","volume":"31","author":"Tabernero","year":"2020","journal-title":"Ann. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1038\/s41571-023-00834-2","article-title":"Personalizing adjuvant therapy for patients with colorectal cancer","volume":"21","author":"Yang","year":"2023","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"177294","DOI":"10.1016\/j.ejphar.2025.177294","article-title":"Beyond chemotherapy: Exploring 5-FU resistance and stemness in colorectal cancer","volume":"991","author":"Singh","year":"2025","journal-title":"Eur. J. Pharmacol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Xie, S., Zhou, Z., Zheng, Y., Yu, C., Kong, W., Chen, Y., Si, W., Zhou, F., Yang, Z., and Ni, R. (2025). Novel drug research and therapeutic strategies targeting tumor metastasis and cancer stem cells. Front. Pharmacol., 16.","DOI":"10.3389\/fphar.2025.1643183"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"175","DOI":"10.3892\/or.2023.8612","article-title":"5-Fluorouracil and capecitabine therapies for the treatment of colorectal cancer (Review)","volume":"50","author":"Alzahrani","year":"2023","journal-title":"Oncol. Rep."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"100754","DOI":"10.1016\/j.drup.2021.100754","article-title":"Therapeutic strategies to overcome taxane resistance in cancer","volume":"55","author":"Das","year":"2021","journal-title":"Drug Resist. Updates"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2075","DOI":"10.1111\/bph.16224","article-title":"Tannins in cancer prevention and therapy","volume":"182","author":"Kleszcz","year":"2023","journal-title":"Br. J. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"154458","DOI":"10.1016\/j.phymed.2022.154458","article-title":"Pharmacological properties of total flavonoids in Scutellaria baicalensis for the treatment of cardiovascular diseases","volume":"107","author":"Tan","year":"2022","journal-title":"Phytomedicine"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4045","DOI":"10.1016\/j.apsb.2021.03.036","article-title":"Baicalin induces ferroptosis in bladder cancer cells by downregulating FTH1","volume":"11","author":"Kong","year":"2021","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e2417022","DOI":"10.1002\/advs.202417022","article-title":"Honokiol-Magnolol-Baicalin Possesses Synergistic Anticancer Potential and Enhances the Efficacy of Anti-PD-1 Immunotherapy in Colorectal Cancer by Triggering GSDME-Dependent Pyroptosis","volume":"12","author":"Gao","year":"2025","journal-title":"Adv. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"105444","DOI":"10.1016\/j.phrs.2021.105444","article-title":"Baicalin and the liver-gut system: Pharmacological bases explaining its therapeutic effects","volume":"165","author":"Hu","year":"2021","journal-title":"Pharmacol. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"114986","DOI":"10.1016\/j.biopha.2023.114986","article-title":"Baicalin enhances the efficacy of 5-Fluorouracil in gastric cancer by promoting ROS-mediated ferroptosis","volume":"164","author":"Yuan","year":"2023","journal-title":"Biomed. Pharmacother."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"117323","DOI":"10.1016\/j.jep.2023.117323","article-title":"A network pharmacology approach and experimental validation to investigate the anticancer mechanism of Qi-Qin-Hu-Chang formula against colitis-associated colorectal cancer through induction of apoptosis via JNK\/p38 MAPK signaling pathway","volume":"319","author":"Wu","year":"2023","journal-title":"J. Ethnopharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"100934","DOI":"10.1016\/j.jpha.2024.01.002","article-title":"Baicalin reduces chronic stress-induced breast cancer metastasis via directly targeting \u03b22-adrenergic receptor","volume":"14","author":"Jia","year":"2024","journal-title":"J. Pharm. Anal."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e2410951","DOI":"10.1002\/advs.202410951","article-title":"A Baicalin-Based Functional Polymer in Dynamic Reversible Networks Alleviates Osteoarthritis by Cellular Interactions","volume":"12","author":"Yang","year":"2025","journal-title":"Adv. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"144799","DOI":"10.1016\/j.ijbiomac.2025.144799","article-title":"Preparation and evaluation of Baicalin-loaded albumin nanoparticles for anti-breast cancer activity","volume":"318","author":"Liu","year":"2025","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_22","first-page":"1933","article-title":"In vitro and in vivo study of Baicalin-loaded mixed micelles for oral delivery","volume":"23","author":"Zhang","year":"2015","journal-title":"Drug Deliv."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1038\/s41568-024-00674-x","article-title":"Immunogenic cell death in cancer: Targeting necroptosis to induce antitumour immunity","volume":"24","author":"Meier","year":"2024","journal-title":"Nat. Rev. Cancer"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1186\/s13045-020-00946-7","article-title":"Ferroptosis, necroptosis, and pyroptosis in anticancer immunity","volume":"13","author":"Tang","year":"2020","journal-title":"J. Hematol. Oncol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3820","DOI":"10.1158\/1078-0432.CCR-12-3289","article-title":"Inhibition of GSK3B bypass drug resistance of p53-null colon carcinomas by enabling necroptosis in response to chemotherapy","volume":"19","author":"Grassilli","year":"2013","journal-title":"Clin. Cancer Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e2010","DOI":"10.1038\/cddis.2015.354","article-title":"Neuroblastoma: Oncogenic mechanisms and therapeutic exploitation of necroptosis","volume":"6","author":"Nicolai","year":"2015","journal-title":"Cell Death Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1038\/s41580-023-00689-6","article-title":"A guide to cell death pathways","volume":"25","author":"Yuan","year":"2023","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/j.molcel.2023.11.040","article-title":"The biochemical pathways of apoptotic, necroptotic, pyroptotic, and ferroptotic cell death","volume":"84","author":"Ai","year":"2024","journal-title":"Mol. Cell"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1126\/science.abg5251","article-title":"Z-DNA binding protein 1 promotes heatstroke-induced cell death","volume":"376","author":"Yuan","year":"2022","journal-title":"Science"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1038\/nature14191","article-title":"Necroptosis and its role in inflammation","volume":"517","author":"Pasparakis","year":"2015","journal-title":"Nature"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1016\/j.immuni.2024.02.011","article-title":"Gasdermin and MLKL necrotic cell death effectors: Signaling and diseases","volume":"57","author":"Lawlor","year":"2024","journal-title":"Immunity"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1038\/s41586-019-1548-x","article-title":"Cleavage of RIPK1 by caspase-8 is crucial for limiting apoptosis and necroptosis","volume":"574","author":"Newton","year":"2019","journal-title":"Nature"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Pettersen, C.H.H., Samdal, H., S\u00e6trom, P., Wibe, A., Hermansen, E., and Sch\u00f8nberg, S.A. (2023). The Salmon Oil OmeGo Reduces Viability of Colorectal Cancer Cells and Potentiates the Anti-Cancer Effect of 5-FU. Mar. Drugs, 21.","DOI":"10.3390\/md21120636"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Li, H., Wang, B., and Wang, Y. (2022). 2\u2032-Fucosyllactose Suppresses Angiogenesis and Alleviates Toxic Effects of 5-Fu in a HCT116 Colon Tumor-Bearing Model. Molecules, 27.","DOI":"10.3390\/molecules27217255"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1007\/s10495-025-02084-2","article-title":"The impact of SEC23A on 5-FU chemotherapy sensitivity and its involvement in endoplasmic reticulum stress-induced apoptosis in colorectal cancer","volume":"30","author":"Su","year":"2025","journal-title":"Apoptosis"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1038\/s41557-021-00711-4","article-title":"Switching on prodrugs using radiotherapy","volume":"13","author":"Geng","year":"2021","journal-title":"Nat. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1038\/s41419-025-07436-z","article-title":"Inactivation of necroptosis-promoting protein MLKL creates a therapeutic vulnerability in colorectal cancer cells","volume":"16","author":"Jiang","year":"2025","journal-title":"Cell Death Dis."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1007\/s12272-022-01397-z","article-title":"Latest research progress on anticancer effect of baicalin and its aglycone baicalein","volume":"45","author":"Wang","year":"2022","journal-title":"Arch. Pharm. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"117127","DOI":"10.1016\/j.jep.2023.117127","article-title":"Efficacy and safety of the traditional herbal medication Chai-Ling-Tang (in China), Siryung-tang (in Republic of Korea) or Sairei-To (in Japan)","volume":"319","author":"Bailly","year":"2023","journal-title":"J. Ethnopharmacol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2015","DOI":"10.1016\/j.ccell.2024.10.014","article-title":"Interleukin-1\u03b1 release during necrotic-like cell death generates myeloid-driven immunosuppression that restricts anti-tumor immunity","volume":"42","author":"Li","year":"2024","journal-title":"Cancer Cell"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1038\/s41419-024-06801-8","article-title":"Necroptosis stimulates interferon-mediated protective anti-tumor immunity","volume":"15","author":"Rucker","year":"2024","journal-title":"Cell Death Dis."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/6\/2919\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T05:37:31Z","timestamp":1774417051000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/6\/2919"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,23]]},"references-count":41,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["ijms27062919"],"URL":"https:\/\/doi.org\/10.3390\/ijms27062919","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,23]]}}}