MicroRNAs in Liver Fibrosis: Unraveling Intercellular Crosstalk and the Regulatory Functions of MicroRNA-223

Abstract

Liver fibrosis is caused by excessive extracellular matrix accumulation, which in turn is driven by activation of hepatic stellate cells. MicroRNAs (miRNAs), a class of small non-coding RNAs, are increasingly recognized as crucial regulators of gene expression in liver pathology, including fibrosis, by influencing intercellular crosstalk. Among these miRNAs, microRNA-223 (miR-223) has emerged as a key regulator of fibrosis, beyond its originally recognized role in innate immunity. By traveling between liver cell types via exosomes, miR-223 modulates inflammation and fibrosis via Hedgehog, platelet-derived growth factor (PDGF), and transforming growth factor-β signaling, and additionally dampens hepatic stellate cell activation by repressing glioma-associated oncogene homolog 2, PDGF receptor β, α-smooth muscle actin, and autophagy related 7, thereby influencing mechanotransduction and autophagy. However, numerous studies have reported opposite results, in which miR-223 promotes fibrosis under certain conditions, thus underscoring the roles of cellular environments, expression levels, and competing RNA networks. This Commentary synthesizes the current, sometimes contradictory, evidence; outlines how context shapes miR-223’s dual actions; and surveys the development of therapeutic strategies, including miRNA mimics, nanoparticle formulations, and extracellular-vesicle delivery, including major challenges in tissue targeting, cargo stability, and long-term safety. These insights together highlight miR-223 as a complex but intriguing target for antifibrotic treatment.

Keywords

Extracellular vesicles / hepatic stellate cell / liver fibrosis / microRNA-223 / miR-223 / non-coding RNA

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