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  • Circular RNAs in Hepatocellular Carcinoma: Molecular Mechanisms, Tumor Microenvironment, Therapeutic Resistance, and Clinical Potential

  • Nasrin Ashoory Shammami,1,* Shokoofeh Salkhordeh,2


  • Introduction: Circular RNAs (circRNAs) are stable, covalently closed RNA molecules generated mainly by back-splicing, in which a downstream 5′ splice donor joins an upstream 3′ splice acceptor. Unlike linear RNAs, most circRNAs lack free 5′ and 3′ termini, a 5′ cap, and a 3′ poly(A) tail. This structure increases resistance to exonuclease-mediated degradation and supports persistence in cells and biological fluids. Their expression is often tissue-, cell-, developmental-, and disease-specific. CircRNAs regulate gene expression through interactions with microRNAs, RNA-binding proteins, transcriptional machinery, and translational components. In hepatocellular carcinoma (HCC), dysregulated circRNAs are associated with proliferation, apoptosis, epithelial-to-mesenchymal transition, invasion, metastasis, angiogenesis, metabolic reprogramming, immune escape, and therapeutic resistance. This review summarizes circRNA biogenesis, molecular functions, and HCC-related roles, emphasizing signaling axes, tumor-microenvironment communication, therapeutic resistance, and biomarker and therapeutic potential.
  • Methods: The reviewed studies identify circRNAs as multifunctional regulatory molecules whose formation depends on precursor-RNA structure, complementary sequences within flanking introns, and RNA-binding proteins. Inverted repetitive elements, particularly Alu sequences, can bring distant splice sites into proximity and facilitate circularization. RNA binding proteins such as Quaking and Muscleblind promote the formation of specific circRNAs, whereas ADAR1 and DHX9 may inhibit circularization by disrupting intronic RNA duplexes. Exonic circRNAs are generally enriched in the cytoplasm, while intron-containing circRNAs are more frequently retained in the nucleus. Consequently, nuclear circRNAs can regulate transcription and alternative splicing, whereas cytoplasmic circRNAs participate in post transcriptional regulation, protein interactions, and translation.
  • Results: The most frequently reported molecular function of circRNAs is their interaction with microRNAs. Through microRNA response elements, circRNAs may act as competing endogenous RNAs and modify the expression of microRNA target genes. However, this mechanism is not applicable to every circRNA. Its biological significance depends on circRNA abundance, the number and accessibility of functional binding sites, microRNA concentration, and the abundance of competing transcripts. CDR1as, which contains numerous binding sites for miR-7, is a representative example of this regulatory mechanism. CircRNAs can also interact directly with RNA-binding and signaling proteins. Some function as protein decoys, whereas others act as molecular scaffolds that bring several proteins into proximity and facilitate regulatory complexes. In addition, selected circRNAs contain internal ribosome entry sites or N6-methyladenosine-associated motifs that enable cap-independent translation and the production of proteins or peptides with potentially distinct functions. In HCC, circRNA expression is extensively altered in tumor tissues, cell lines, blood samples, and extracellular vesicles. These changes influence several aspects of tumor biology through specific molecular pathways. For example, circMAT2B promotes hypoxia-associated glycolytic reprogramming through the miR-338-3p/PKM2 axis, thereby supporting the Warburg effect and tumor growth. Circβ-catenin can encode a functional β-catenin isoform that enhances Wnt/β-catenin signaling. Other HCC-associated circRNAs regulate the PI3K/AKT/mTOR, MAPK, JAK/STAT, and Hippo pathways, affecting proliferation, apoptosis, epithelial-to-mesenchymal transition, invasion, metastasis, and angiogenesis.
  • Conclusion: Overall, the reviewed evidence indicates that circRNAs are not passive by-products of abnormal splicing but active regulators of HCC progression. Their covalently closed structure enables them to persist in tissues, plasma, serum, and exosomes, while their interactions with microRNAs, proteins, transcriptional machinery, and translational components connect RNA regulation with oncogenic signaling, metabolic adaptation, immune escape, tumor microenvironment communication, and treatment failure. Accordingly, circRNAs have dual significance in HCC. They may function as minimally invasive diagnostic, prognostic, and treatment-monitoring biomarkers because of their stability, disease associated expression, tissue specificity, and detectability in circulating fluids and extracellular vesicles. They may also provide therapeutic targets through inhibition of oncogenic circRNAs, restoration of tumor-suppressive circRNAs, disruption of circRNA–microRNA or circRNA–protein interactions, or inhibition of exosomal circRNA transfer. Nevertheless, promising molecular findings do not yet establish clinical utility. Differences in nomenclature, sample processing, detection platforms, normalization procedures, and the absence of sufficiently large prospective validation studies remain major barriers to clinical translation. Therefore, circRNAs should currently be considered biologically important and clinically promising candidates rather than validated clinical tools. Their application in HCC diagnosis or treatment will require standardized detection methods, rigorous functional validation, and well-designed clinical studies capable of determining which circRNAs possess reproducible, disease-specific, and clinically actionable value.
  • Keywords: Circular RNAs, Hepatocellular carcinoma, Tumor microenvironment, Therapeutic resistance

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