Decoding circRNA-miRNA crosstalk in the pathogenesis of hepatic fibrosis: A comprehensive review

Hepatic fibrosis is a pathological condition characterized by persistent activation of hepatic stellate cells and the deposition of extracellular matrix components. It can occur due to various reasons, including viral infection, metabolic dysfunction, radiation exposure, cholestatic disorders, and environmental toxicants. Emerging evidence indicates that circular RNAs (circRNAs) strongly influence fibrosis by modulating microRNA (miRNA) activity and downstream signaling pathways, yet little research has been done on this topic. This comprehensive review systematically evaluates and synthesizes current evidence on circRNA-miRNA-mediated regulatory networks in liver fibrosis, with a primary focus on their mechanistic roles in driving fibrogenesis. To address this, a comprehensive and systematic search was conducted across the PubMed, Web of Science, and Scopus databases for research articles published between 2015 and 2025, following PRISMA guidelines. We identified 30 eligible studies that showcase validated circRNA-mediated regulatory interactions in vitro, in vivo, and in hepatic fibrosis patient samples. 16 circRNAs were found to be profibrotic, and 14 circRNAs were identified as antifibrotic modulating various signaling pathways. TGF-β and PI3K/AKT were the major signaling pathways identified among the circRNAs that modulate fibrosis and drive its progression. Bioinformatic and network analysis were used to validate and identify molecular targets that could play a role in disease progression. Future efforts should focus on validating circRNA expression in patient samples to help identify therapeutic strategies across its diverse etiologies. Beyond miRNA sponging, other non-canonical regulatory roles, such as interactions with RNA- binding proteins and epigenetic regulators, are yet to be fully explored.