image: Image Caption: Part 1: The process of HBV infection and replication in cells: (A) HBV enters the liver cell via fusion and endocytosis. Image link: https://ars.els-cdn.com/content/image/1-s2.0-S2352304225000947-gr1_lrg.jpg
Credit: Genes & Diseases
Hepatitis B virus-induced hepatocellular carcinoma (HCC) remains a major global health burden, and new therapeutic and diagnostic approaches are urgently needed. Emerging research highlights the crucial role of circular RNAs (circRNAs) in disease progression, offering promising avenues for early detection and innovative treatments. These non-coding RNA molecules, known for their stability and regulatory functions, are proving to be pivotal in tumor biology and immune response modulation.
Unlike linear RNAs, circRNAs have a closed-loop structure that makes them resistant to degradation, allowing them to serve as long-lasting regulators of gene expression. They influence multiple cancer-related processes, including tumor proliferation, metastasis, immune evasion, and drug resistance. Specific circRNAs such as circRNA-100338, circRNA-101764, and circBACH1 have been identified as key players in HCC progression, affecting crucial signaling pathways like PI3K/Akt, Wnt/β-catenin, and NF-κB. By acting as molecular sponges for microRNAs (miRNAs), these circRNAs help modulate cancer-promoting genes, making them attractive targets for therapeutic intervention.
The potential of circRNAs extends beyond treatment to early diagnosis and prognostic evaluation. Blood-based biomarkers, including circRNA panels, have demonstrated high specificity and sensitivity in distinguishing HCC from chronic hepatitis B and cirrhosis, outperforming traditional markers like alpha-fetoprotein (AFP). With liquid biopsy techniques gaining traction, circRNAs could revolutionize non-invasive cancer detection, enabling early intervention and improved patient outcomes.
Targeting circRNAs for therapy is an exciting frontier in RNA-based medicine. Cutting-edge approaches, including RNA interference (RNAi), CRISPR-based gene editing, and nanoparticle delivery systems, are being explored to selectively suppress tumor-promoting circRNAs or restore tumor-suppressive ones. Additionally, circRNA-based vaccines are under development, leveraging their ability to encode therapeutic proteins while avoiding rapid degradation.
Advancements in high-throughput sequencing and bioinformatics are accelerating circRNA research, providing deeper insights into their functional mechanisms in liver cancer. However, challenges remain in translating these findings into clinical applications, including the need for precise delivery systems, validation in large-scale studies, and better understanding of circRNA interactions with host immune pathways.
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Reference
Wenjun Quan, Kizito Eneye Bello, Rafidah Hanim Shueb, Nazri Mustaffa, Circular RNAs in hepatitis B virus-induced hepatocellular carcinoma: A comprehensive review and recent advances, Genes & Diseases, Volume 12, Issue 5, 2025, 101605, https://doi.org/10.1016/j.gendis.2025.101605
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Genes & Diseases