Circular RNAs as diagnostic biomarkers and therapeutic regulators of metabolic reprogramming, immune escape and ferroptosis in hepatocellular carcinoma.

Abstract

Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related mortality worldwide, largely due to delayed diagnosis, high recurrence rates, therapeutic resistance, and marked molecular heterogeneity. The identification of reliable biomarkers for early detection, prognostic stratification, and therapeutic monitoring is therefore of considerable clinical importance. Circular RNAs (circRNAs), a class of highly stable covalently closed non-coding RNAs, have emerged as promising molecular biomarkers owing to their tissue specificity, evolutionary conservation, and detectability in body fluids and extracellular vesicles. Accumulating evidence indicates that circRNAs play pivotal roles in hepatocarcinogenesis by regulating key biological processes, including metabolic reprogramming, immune evasion, and ferroptosis. Through ceRNA networks, epigenetic modulation, and interactions with RNA-binding proteins, circRNAs orchestrate glycolytic metabolism, lipid metabolic pathways, hypoxia adaptation, immune checkpoint signaling, tumor-associated macrophage polarization, and ferroptosis-associated antioxidant defenses. These regulatory functions not only contribute to tumor progression but also influence sensitivity to systemic therapies and immunotherapeutic interventions. Beyond their mechanistic roles, numerous circRNAs have demonstrated significant diagnostic and prognostic potential in HCC. Circulating and exosomal circRNAs are increasingly recognized as attractive liquid biopsy candidates because of their remarkable stability and accessibility in clinical specimens. Furthermore, specific circRNA signatures have been associated with tumor aggressiveness, recurrence risk, immune landscape remodeling, and treatment response, highlighting their utility as predictive biomarkers and potential therapeutic targets. In this review, we comprehensively summarize the current understanding of circRNA-mediated regulation of metabolic reprogramming, immune escape, and ferroptosis in HCC, with particular emphasis on their clinical and translational relevance. We further discuss the emerging role of circRNAs as diagnostic, prognostic, and predictive biomarkers, as well as the challenges that must be addressed before their integration into routine clinical practice. Collectively, circRNAs represent a promising class of biomolecules with substantial potential to improve precision diagnostics and personalized management of hepatocellular carcinoma.