Baicalin Augments 5-Fluorouracil Efficacy in Colorectal Cancer by Triggering MLKL-Dependent Necroptosis: A Novel Strategy to Overcome Chemoresistance

Yuan, Jingwen; Peng, Zhiying; Wen, Rongbo; Zhou, Leqi; Cao, Fuao; Zhang, Tianshuai; Wu, Yingjie; Wu, Jiayue; Lin, Ran; Yu, Guanyu; Zhang, Wei

doi:10.3390/ijms27062919

Open AccessArticle

Baicalin Augments 5-Fluorouracil Efficacy in Colorectal Cancer by Triggering MLKL-Dependent Necroptosis: A Novel Strategy to Overcome Chemoresistance

by

Jingwen Yuan

^†

,

Zhiying Peng

^†,

Rongbo Wen

,

Leqi Zhou

,

Fuao Cao

,

Tianshuai Zhang

,

Yingjie Wu

,

Jiayue Wu

,

Ran Lin

,

Guanyu Yu

^*

and

Wei Zhang

^*

Colorectal Surgery Department, Changhai Hospital, Naval Medical University, Shanghai 200433, China

^*

Authors to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

Int. J. Mol. Sci. 2026, 27(6), 2919; https://doi.org/10.3390/ijms27062919

Submission received: 2 February 2026 / Revised: 15 March 2026 / Accepted: 20 March 2026 / Published: 23 March 2026

(This article belongs to the Special Issue Anti-Cancer Drugs: Natural Products, Synthetic Compounds and Potential Pharmacological Effects and Applications)

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Abstract

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.

Keywords: baicalin; 5-fluorouracil; colorectal cancer; necroptosis; chemoresistance

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MDPI and ACS Style

Yuan, J.; Peng, Z.; Wen, R.; Zhou, L.; Cao, F.; Zhang, T.; Wu, Y.; Wu, J.; Lin, R.; Yu, G.; et al. Baicalin Augments 5-Fluorouracil Efficacy in Colorectal Cancer by Triggering MLKL-Dependent Necroptosis: A Novel Strategy to Overcome Chemoresistance. Int. J. Mol. Sci. 2026, 27, 2919. https://doi.org/10.3390/ijms27062919

AMA Style

Yuan J, Peng Z, Wen R, Zhou L, Cao F, Zhang T, Wu Y, Wu J, Lin R, Yu G, et al. Baicalin Augments 5-Fluorouracil Efficacy in Colorectal Cancer by Triggering MLKL-Dependent Necroptosis: A Novel Strategy to Overcome Chemoresistance. International Journal of Molecular Sciences. 2026; 27(6):2919. https://doi.org/10.3390/ijms27062919

Chicago/Turabian Style

Yuan, Jingwen, Zhiying Peng, Rongbo Wen, Leqi Zhou, Fuao Cao, Tianshuai Zhang, Yingjie Wu, Jiayue Wu, Ran Lin, Guanyu Yu, and et al. 2026. "Baicalin Augments 5-Fluorouracil Efficacy in Colorectal Cancer by Triggering MLKL-Dependent Necroptosis: A Novel Strategy to Overcome Chemoresistance" International Journal of Molecular Sciences 27, no. 6: 2919. https://doi.org/10.3390/ijms27062919

APA Style

Yuan, J., Peng, Z., Wen, R., Zhou, L., Cao, F., Zhang, T., Wu, Y., Wu, J., Lin, R., Yu, G., & Zhang, W. (2026). Baicalin Augments 5-Fluorouracil Efficacy in Colorectal Cancer by Triggering MLKL-Dependent Necroptosis: A Novel Strategy to Overcome Chemoresistance. International Journal of Molecular Sciences, 27(6), 2919. https://doi.org/10.3390/ijms27062919

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Baicalin Augments 5-Fluorouracil Efficacy in Colorectal Cancer by Triggering MLKL-Dependent Necroptosis: A Novel Strategy to Overcome Chemoresistance

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