Sirtuin 1-microRNA regulatory networks in liver diseases: Mechanistic convergence, cellular senescence, and...

Metabolic dysfunction-associated steatotic liver disease, hepatotoxicity, liver fibrosis, and hepatocellular carcinoma are stages of chronic liver injury that occur in the setting of complex interactions of the various factors, including metabolic dysregulation, inflammation, oxidative stress, and cellular senescence. Recent studies propose that microRNAs (miRNAs), regulators of these processes, act through modulation of sirtuin 1 (SIRT1), a key metabolic and stress-response sensor recognizing the organism's needs under various physiological and pathological conditions. Abnormalities in the SIRT1-miRNA network function are implicated in processes of lipid accumulation, mitochondrial dysfunction, immune-cell activation, stellate-cell transdifferentiation, fibrogenesis, and tumor development. In the present review, we make an attempt to carry out joint analysis of SIRT1-miRNA interaction throughout the history of liver diseases. In contrast to the previously existing reviews focusing on independent miRNAs and diseases independently, we focus on the idea of mechanistic convergence and the specificity of how SIRT1 works in different disease stages. We also consider novel ideas, including the concept of cellular senescence, immunometabolic switch, communication through exosomes, and the role of SIRT1 in hepatocellular carcinoma development. We analyze the way the regulation of SIRT1 by miRNA affects metabolic adaptation and fibrogenesis. Although experimental studies consistently support the biological significance of the SIRT1-miRNA axis, important translational challenges remain, including disease heterogeneity, cell-specific targeting, delivery limitations, and insufficient clinical validation. Future integration of multiomics technologies, circulating miRNA biomarkers, and precision-medicine approaches may improve understanding of SIRT1-centered regulatory networks and facilitate the development of more effective therapeutic strategies for liver diseases. SIGNIFICANCE STATEMENT: By investigating the intricacies of sirtuin 1-microRNA (SIRT1-miRNA) regulatory mechanisms, valuable knowledge is gained regarding the role of SIRT1 post-transcriptional regulation in causing metabolic disorders, inflammation, fibrosis, and progression of hepatocellular carcinoma. The article also highlights serious pharmacological challenges in this area, such as specificity of treatment, possible influence of drugs on other mechanisms of the body, and ability to separate the beneficial effects of SIRT1 activation in the case of metabolic liver disease from its harmful effects in more advanced cases of hepatocellular carcinoma.