Targeting circular RNAs to overcome therapeutic resistance in liver cancer: from mechanisms to clinical prospects
4 affiliations
- 1Department of Liver Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
- 2Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China
- 3Division of Biliary Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China
- 4Research Center for Biliary Diseases, West China Hospital, Sichuan University, Chengdu, China
Abstract
Primary liver cancer, including hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), remains a leading cause of cancer-related death worldwide. Therapeutic resistance substantially limits the efficacy of chemotherapy, targeted therapy, immunotherapy, and radiotherapy. For example, only approximately 30% of patients with HCC derive clinical benefit from sorafenib, and acquired resistance commonly develops within six months, underscoring the urgent need to clarify the molecular basis of treatment failure. Circular RNAs (circRNAs) are covalently closed RNA molecules with high structural stability and tissue-specific expression. In liver cancer, circRNAs regulate therapeutic resistance through multiple mechanisms that converge on ferroptosis suppression, apoptosis evasion, DNA damage repair, oncogenic signaling, immune escape, and cancer stemness. Beyond the canonical competing endogenous RNA model, this review highlights emerging regulatory mechanisms involving RNA-binding protein interactions, circRNA-encoded functional micropeptides, and circRNA-mediated phase separation. Exosomal circRNAs also facilitate the intercellular transmission of resistant phenotypes and remodel the tumor immune microenvironment. We systematically summarize circRNA-mediated resistance across different therapeutic modalities and critically evaluate the available evidence according to experimental models, in vivo validation, and patient validation. Although circRNAs show potential as biomarkers for predicting therapeutic response and as targets for overcoming resistance, most candidates remain at the preclinical stage. Their clinical translation is constrained by the lack of standardized detection methods, insufficient multicenter validation, and inefficient and inadequately targeted in vivo delivery systems. Because most direct mechanistic evidence is derived from HCC, selected iCCA-related findings are incorporated where available.
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BibTeX
@article{zhou2026targeting,
title = {{Targeting circular RNAs to overcome therapeutic resistance in liver cancer: from mechanisms to clinical prospects}},
author = {Xinyi Zhou and Chenyu Yang and Jiong Lu and Tengda Huang and Shiqi Ren and Hongyuan Pan and Ao Du and Zhixiang Zhou and Kefei Yuan},
journal = {Molecular Cancer},
year = {2026},
month = jul,
doi = {10.1186/s12943-026-02761-z},
url = {https://doi.org/10.1186/s12943-026-02761-z},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Targeting circular RNAs to overcome therapeutic resistance in liver cancer: from mechanisms to clinical prospects
AU - Xinyi Zhou
AU - Chenyu Yang
AU - Jiong Lu
AU - Tengda Huang
AU - Shiqi Ren
AU - Hongyuan Pan
AU - Ao Du
AU - Zhixiang Zhou
AU - Kefei Yuan
PY - 2026
DA - 2026/07/31
JO - Molecular Cancer
DO - 10.1186/s12943-026-02761-z
UR - https://doi.org/10.1186/s12943-026-02761-z
AB - Primary liver cancer, including hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), remains a leading cause of cancer-related death worldwide. Therapeutic resistance substantially limits the efficacy of chemotherapy, targeted therapy, immunotherapy, and radiotherapy. For example, only approximately 30% of patients with HCC derive clinical benefit from sorafenib, and acquired resistance commonly develops within six months, underscoring the urgent need to clarify the molecular basis of treatment failure. Circular RNAs (circRNAs) are covalently closed RNA molecules with high structural stability and tissue-specific expression. In liver cancer, circRNAs regulate therapeutic resistance through multiple mechanisms that converge on ferroptosis suppression, apoptosis evasion, DNA damage repair, oncogenic signaling, immune escape, and cancer stemness. Beyond the canonical competing endogenous RNA model, this review highlights emerging regulatory mechanisms involving RNA-binding protein interactions, circRNA-encoded functional micropeptides, and circRNA-mediated phase separation. Exosomal circRNAs also facilitate the intercellular transmission of resistant phenotypes and remodel the tumor immune microenvironment. We systematically summarize circRNA-mediated resistance across different therapeutic modalities and critically evaluate the available evidence according to experimental models, in vivo validation, and patient validation. Although circRNAs show potential as biomarkers for predicting therapeutic response and as targets for overcoming resistance, most candidates remain at the preclinical stage. Their clinical translation is constrained by the lack of standardized detection methods, insufficient multicenter validation, and inefficient and inadequately targeted in vivo delivery systems. Because most direct mechanistic evidence is derived from HCC, selected iCCA-related findings are incorporated where available.
SN - 1476-4598
ER -