Methyl-cantharidimide suppresses cyclin-dependent kinase 1 (CDK1) and induces oxeiptosis in liver cancer

Sep 22, 2026

Methyl-cantharidimide (MCA), a cantharidin analog approved in China for liver cancer, was investigated to clarify anticancer mechanisms. MCA inhibited colony formation in liver cancer cell lines and downregulated cyclin-dependent kinase 1 (CDK1), supporting cell cycle arrest. MCA elevated intracellular reactive oxygen species and triggered apoptosis through a ROS-dependent oxeiptosis pathway instead of a caspase-dependent mechanism. Effects persisted in a 3D multicellular tumor spheroid model and reduced tumor size in a HepG2 xenograft mouse model.

LanguageEnglish

CategoryHealthcare

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Pages14

Reading Time35 min

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Abstract

Background

Methods

Results

Conclusions

Introduction

Cancer burden and liver cancer risk factors

Cantharidin background and anticancer activity

Li et al. Journal of Experimental & Clinical Cancer Research (2026) 45:90 [https://doi.org/10.1186/s13046-026-03669-8](https://doi.org/10.1186/s13046-026-03669-8) Journal of Experimental & Clinical Cancer Research RESEARCH Open Access Methyl-cantharidimide suppresses cyclindependent kinase 1 (CDK1) and inducesoxeiptosis in liver cancer Yi-Dong Li1, Xiang Chen1, Xing-Duo Dong1, Zhiyong Ding2, Zhe-Sheng Chen1* and Shuo Fang3* Abstract Background Methyl-cantharidimide (MCA), a cantharidin (CTD) analog, has been approved in China for the clinical treatment of liver cancer. Previous studies have shown that MCA can induce both apoptosis and cell cycle arrest in cancer cells. However, the precise molecular mechanisms underlying its anticancer activity remain largely unclear. Methods The effects of MCA were evaluated in liver cancer cell lines using colony formation assays. Bioinformatic analysis was performed to explore molecular mechanisms, with validation via immunoblotting and immunofluorescence. Reactive oxygen species (ROS) production was measured to assess oxidative stress induction. A 3D multicellular tumor spheroid (MCTS) model was used to mimic tumor-like in vitro conditions, and a HepG2 xenograft mouse model was employed to investigate in vivo efficacy. Results MCA significantly inhibited colony formation in liver cancer cells. Bioinformatic profiling suggested that downregulation of cyclin-dependent kinase 1 (CDK1) may mediate MCA-induced cell cycle arrest, which was confirmed by suppressed CDK1 expression in both immunoblotting and immunofluorescence assays. MCA also increased intracellular ROS levels. Further analyses revealed that MCA-induced apoptosis occurred through a ROSdependent oxeiptosis pathway, rather than the conventional caspase-dependent route. In the MCTS model, MCA maintained its cytotoxicity, demonstrating efficacy under more physiologically relevant conditions. In the in vivo xenograft mouse model, MCA treatment led to a significant reduction in tumor size. Conclusions MCA exerts anticancer effects in liver cancer cells by inducing cell cycle arrest via CDK1 downregulation and promoting apoptosis through a ROS-dependent oxeiptosis pathway. These findings provide mechanistic insight into MCA’s antitumor activity and support its potential as a therapeutic agent for liver cancer. Keywords Methyl-cantharidimide (MCA), Liver cancer, CDK1, Oxeiptosis *Correspondence: Zhe-Sheng Chen[chenz@stjohns.edu](chenz@stjohns.edu)[ ](chenz@stjohns.edu)Shuo Fang [fangsh9@mail.sysu.edu.cn](fangsh9@mail.sysu.edu.cn) 1Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, NY 11439, USA 2Institute for Personalized Cancer Care, Fynn Biotechnologies Ltd., Jinan City, Shandong 250101, PR China 3Department of Oncology, The Seventh Affiliated Hospital, SunYat-sen University, Shenzhen, Guangdong 518107, PR China © The Author(s) 2026. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://creativecommons.org/licenses/by/4.0/](http://creativecommons.org/licenses/by/4.0/. The)[. The](http://creativecommons.org/licenses/by/4.0/. The)[ ](http://creativecommons.org/licenses/by/4.0/. The)Creative Commons Public

FAQs

What anticancer effects does methyl-cantharidimide show in liver cancer models?

MCA significantly inhibits colony formation in liver cancer cells, maintains cytotoxicity in a 3D multicellular tumor spheroid model, and reduces tumor size in a HepG2 xenograft mouse model.

How does MCA affect the cell cycle in liver cancer cells?

Bioinformatic profiling and experiments indicate that MCA downregulates CDK1, which mediates MCA-induced cell cycle arrest.

What mechanism connects MCA treatment to apoptosis?

MCA increases intracellular ROS and induces apoptosis via a ROS-dependent oxeiptosis pathway, rather than the conventional caspase-dependent route.

Sep 22, 2026

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