RNA Interference as a Method for Validation of Pharmacological Targets in Fibrosis Treatment

Abstract— RNA interference (RNAi) is an evolutionarily conserved mechanism of gene expression silencing based on the degradation of mRNA by small interfering RNAs (siRNAs). The discovery of this mechanism has not only become a powerful tool for fundamental research in biology, but has also opened up new perspectives for therapeutic medicine. In terms of efficacy and safety, siRNA therapy represents a promising alternative to traditional pharmaceutical approaches, which are often characterized by systemic toxicity and low specificity. siRNA-based therapy allows for the selective suppression of genes associated with pathologies, providing high specificity and low toxicity. The use of siRNA to modulate the activity of macrophages, key effectors of innate immunity that play a central role in the development of liver fibrosis, represents particular interest. Due to their high plasticity, macrophages are able to polarize into proinflammatory (M1) or anti-inflammatory (M2) phenotypes, which determines their contribution to the progression or regression of fibrosis. Suppression of key polarization regulators (such as EGR2, IRF5, IRF3, TLR4, HAS2) using siRNA allows macrophage repolarization into alternative functional phenotypes. This review systematizes current data on the role of macrophages in the pathogenesis of liver fibrosis and the prospects for using siRNA therapy to control their activity. Strategies for precision targeting of key molecular targets are discussed, opening up new possibilities for the development of pathogenetically justified treatment methods.