CircRNAs Crosstalk with Key Signaling Proteins in the Progression of Hepatocellular Carcinoma

Hepatocellular Carcinoma (HCC) represents one of the most prevalent and lethal malignancies worldwide, posing a significant global health challenge with increasing incidence and poor prognosis. Aberrant expression of circular RNAs (circRNAs) has emerged as a critical factor in HCC pathogenesis, positioning them as promising biomarkers and novel therapeutic targets. CircRNAs exert profound influence on diverse cellular processes by interacting with key signaling pathways essential for cell proliferation, immune evasion, and metabolic homeostasis. Their functional roles encompass promoting cancer cell growth, metastasis, invasion, Epithelial-Mesenchymal Transition (EMT), metabolic reprogramming, and tumor angiogenesis, as depicted in Fig. (1). A central focus of this review is deciphering the mechanistic interplay between circRNAs and these pathways, including the Wnt/βcatenin, PI3K/Akt, and MAPK pathways. CircRNAs dynamically regulate gene expression by acting as competing endogenous RNAs (ceRNAs) that sponge microRNAs (miRNAs) to modulate messenger RNA (mRNA) stability and translation-reflecting the current predominance of ceRNA-focused studies in the field-while direct protein interactions and correlative expression with signaling pathways represent less explored but critical modes of crosstalk. This interaction forms intricate molecular networks that critically govern HCC progression, as outlined in Fig. (2). Specific examples, such as the tumor-suppressive circMTO1 (inhibits proliferation via miR-195-5p) and circZKSCAN1 (which inhibits HCC progression through multiple signaling pathways and enhances sorafenib sensitivity), illustrate the critical tumor-suppressive roles of circRNAs in HCC. While challenges remain in clinical application, including standardization of detection methods and delivery systems for therapy, the potential for circRNA-based diagnostics and therapeutics is significant, though still in the preclinical stage. The exploration of circular RNAs (circRNAs) in liquid biopsies presents a promising avenue for early detection and personalized medicine. This review comprehensively summarizes the current understanding of circRNAs in HCC, covering their roles in disease initiation and progression, their prognostic value, and their emerging potential as both non-invasive biomarkers and targeted therapeutic agents.