MicroRNAs in Renal Fibrosis: Unraveling Mechanisms and Therapeutic Potential

Chronic Kidney Disease (CKD) poses a growing global health burden, with increasing prevalence driven by risk factors such as aging, metabolic disorders, and environmental influences. As CKD progresses, it frequently leads to renal fibrosis, a pathological condition characterized by excessive extracellular matrix (ECM) accumulation, fibroblast activation, and progressive loss of kidney function, ultimately resulting in end-stage renal disease (ESRD). Despite advances in CKD management, effective therapies to prevent or reverse renal fibrosis remain limited, underscoring the need for innovative therapeutic strategies. MicroRNAs (miRNAs), small non-coding RNA molecules, have emerged as important post-transcriptional regulators of molecular pathways underlying renal fibrosis. These molecules regulate gene expression and participate in critical processes, including fibroblast activation, ECM remodeling, and inflammation, which collectively contribute to CKD progression. Accordingly, miRNAs are promising biomarkers and therapeutic targets, with urinary and circulating miR-21-5p, miR-192-5p, members of the miR-29 family, miR-126, and miR-210 demonstrating potential clinical relevance. This review examines the role of miRNAs in renal fibrosis and CKD progression, with emphasis on fibroblast activation, partial epithelial-mesenchymal transition (EMT)-associated epithelial plasticity, and ECM deposition. Current evidence indicates that miR-21-5p, miR-433-3p, miR-324-3p, and miR-214-3p generally promote profibrotic or injury-associated signaling, whereas the miR-29 and let-7 families predominantly exert antifibrotic effects. Notably, miR-192-5p and miR-214-3p exhibit context-dependent functions according to renal cell type, disease stage, and molecular target. The review also evaluates miRNA-based therapeutic strategies, including antagomiRs, miRNA mimics, and nanoparticle- and extracellular vesicle-based delivery systems, while addressing persistent challenges related to molecular stability, renal-specific delivery, off-target effects, and clinical translation. Overall, this review advances understanding of miRNA-mediated regulation in CKD and highlights their potential for developing diagnostic and therapeutic approaches to mitigate renal fibrosis and retard CKD progression.