Circular RNAs in hepatocellular carcinoma: a systematic qualitative review of regulatory mechanisms, therapeutic resistance, and clinical translation.

BACKGROUND

Hepatocellular carcinoma (HCC) is characterized by high mortality, frequent recurrence, and limited long-term benefit from systemic therapy and radiotherapy. Circular RNAs (circRNAs), a class of covalently closed non-coding RNAs with high molecular stability and tissue-specific expression, have emerged as important regulators of HCC biology and treatment response.

METHODS

We searched PubMed from database inception to May 2, 2026 and manually screened the reference lists of eligible studies and relevant reviews for studies investigating circRNA-related molecular mechanisms, tumor progression, therapeutic resistance, radiotherapy response, or translational applications in HCC. A total of 694 records were identified in PubMed, 694 records were screened after duplicate removal, and 42 studies were included in the qualitative synthesis. Original studies involving human tissues, clinical cohorts, cell lines, or animal models were eligible. Title/abstract screening, full-text assessment, and data extraction were performed independently by two reviewers, with disagreements resolved by consensus or senior-author adjudication. Given substantial heterogeneity in study design, model systems, molecular endpoints, and reported outcomes, findings were synthesized qualitatively rather than by meta-analysis, and a structured qualitative evidence appraisal was used to weight mechanistic and translational conclusions.

RESULTS

The included evidence indicates that circRNAs participate in HCC progression through miRNA sponging, RNA-binding protein interactions, transcriptional regulation, epigenetic modulation, and, in selected contexts, translational activity. Distinct oncogenic and tumor-suppressive circRNAs converge on pathways related to proliferation, epithelial-mesenchymal transition, metastasis, ferroptosis, stemness, and DNA-damage repair. CircRNAs were also associated with sorafenib and lenvatinib response, radioresistance, and radiosensitivity. Emerging translational applications include tissue and liquid-biopsy biomarkers, especially exosomal circRNAs, as well as junction-targeted oligonucleotide strategies.

CONCLUSIONS

Current evidence supports circRNAs as mechanistically relevant regulators and promising translational candidates in HCC. However, progress toward clinical application is constrained by etiologic heterogeneity, limited standardization, incomplete specificity validation for therapeutic targeting, and the lack of multicenter prospective validation studies.