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已发表论文
EZH2：从肝细胞癌的致癌驱动因子到克服耐药性的治疗靶点
Authors Tang W , Cao J, Wang N, Tang L, Cao J
Received 16 July 2025
Accepted for publication 23 December 2025
Published 31 December 2025 Volume 2025:12 Pages 3091—3104
DOI https://doi.org/10.2147/JHC.S554181
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Prof. Dr. Jörg Trojan
Weijing Tang,1 Jianzhong Cao,1 Nan Wang,2 Liwen Tang,2 Jianxiong Cao1,2
1School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, People’s Republic of China; 2Department of Oncology, the First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, People’s Republic of China
Correspondence: Liwen Tang, Department of Oncology, the First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, People’s Republic of China, Email 2638705707@qq.com Jianxiong Cao, School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, People’s Republic of China, Email sakato1996@163.com
Abstract: Hepatocellular carcinoma (HCC) remains a therapeutic challenge due to the high prevalence of drug resistance. The histone methyltransferase Enhancer of Zeste Homolog 2 (EZH2), a core component of the Polycomb Repressive Complex 2, is frequently overexpressed in HCC and drives of drug resistance. This review delineates the multifaceted mechanisms by which EZH2 promotes resistance to chemotherapy, targeted therapy, and immunotherapy. We detail how EZH2 orchestrates pro-survival pathways by modulating cell cycle checkpoints, inhibiting apoptosis, enhancing DNA repair, and fostering an immunosuppressive tumor microenvironment. Furthermore, we evaluate the current landscape of EZH2 inhibitors, from clinically approved agents to novel therapeutic modalities like PROTACs, and discuss their potential to re-sensitize HCC to treatment. Finally, we outline future research directions, emphasizing combination strategies and biomarker development, to advance EZH2-targeting therapies for HCC.
Keywords: EZH2, hepatocellular carcinoma, mechanisms of drug resistance, epigenetics
1School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, People’s Republic of China; 2Department of Oncology, the First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, People’s Republic of China
Correspondence: Liwen Tang, Department of Oncology, the First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, People’s Republic of China, Email 2638705707@qq.com Jianxiong Cao, School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, People’s Republic of China, Email sakato1996@163.com
Abstract: Hepatocellular carcinoma (HCC) remains a therapeutic challenge due to the high prevalence of drug resistance. The histone methyltransferase Enhancer of Zeste Homolog 2 (EZH2), a core component of the Polycomb Repressive Complex 2, is frequently overexpressed in HCC and drives of drug resistance. This review delineates the multifaceted mechanisms by which EZH2 promotes resistance to chemotherapy, targeted therapy, and immunotherapy. We detail how EZH2 orchestrates pro-survival pathways by modulating cell cycle checkpoints, inhibiting apoptosis, enhancing DNA repair, and fostering an immunosuppressive tumor microenvironment. Furthermore, we evaluate the current landscape of EZH2 inhibitors, from clinically approved agents to novel therapeutic modalities like PROTACs, and discuss their potential to re-sensitize HCC to treatment. Finally, we outline future research directions, emphasizing combination strategies and biomarker development, to advance EZH2-targeting therapies for HCC.
Keywords: EZH2, hepatocellular carcinoma, mechanisms of drug resistance, epigenetics