Circular RNAs at the Crossroads of Inflammation, Fibrosis and Tissue Repair

Abstract

Circular RNAs (circRNAs) are covalently closed RNA molecules generated through back-splicing of precursor mRNA (pre-mRNA) transcripts. Although circRNAs lack the 5′ cap and the 3′ poly(A) tail characteristic of linear mRNAs, their circular structure confers enhanced stability and resistance to exonucleolytic degradation, establishing circRNAs as important regulators of gene expression that contribute to cellular homeostasis and disease progression. CircRNAs regulate gene expression at multiple levels through miRNA sequestration, modulation of RNA-binding protein (RBP) activity, regulation of transcription and splicing, and even translation into functional micropeptides, with emerging evidence supporting their involvement in the splicing machinery. Here, we will review current knowledge on circRNA biogenesis and function, mainly focusing on their impact on the transition from inflammation to tissue repair, fibrotic remodeling, and disease progression. Special attention is devoted to circRNA-mediated regulatory networks in renal disease while placing these findings within the broader context of fibrotic and inflammatory disorders affecting multiple organs. We further examine the potential of circRNAs as stable, tissue-specific biomarkers and therapeutic targets, while highlighting the emerging use of endogenous and engineered circRNAs as platforms for RNA-based therapeutics and vaccines. By integrating mechanistic insights with functional and translational perspectives, this review provides a framework for understanding circRNAs as active components of RNA regulatory networks and outline the key challenges and opportunities for their future clinical translation.