Mol Biol Rep. 2026 Jun 6;53(1):899. doi: 10.1007/s11033-026-12062-9.
ABSTRACT
MicroRNAs (miRNAs) and the NAD+-dependent deacetylase SIRT1 are critical regulators of hepatic metabolism, inflammation, and stress responses. Growing evidence suggests that miRNA-SIRT1 interactions are frequently disrupted during the pathogenesis of liver diseases, including Metabolism-Associated Steatotic Liver Disease (MASLD), Alcohol-Associated Liver Disease, Drug-Induced Liver Injury (DILI), fibrosis, and hepatocellular carcinoma (HCC).In the context of metabolic liver diseases, specific miRNAs, such as miR-122, miR-93, miR-132, miR-34a, and miR-141, regulate lipid and energy metabolism by modulating SIRT1 and its downstream targets, notably AMPK and PGC-1α. Furthermore, miRNAs can suppress SIRT1 activity during liver injury, exacerbating oxidative stress, mitochondrial dysfunction, and inflammation. In HCC, the role of SIRT1 is context-dependent; influenced by the stage of differentiation and genetic factors such as p53, SIRT1 may exert either tumor-suppressive or tumor-promoting effects. While preclinical studies demonstrate the therapeutic potential of targeting the miRNA-SIRT1 pathway, current evidence remains largely experimental. Pharmacological modulation, via SIRT1 activators, small-molecule compounds, or RNA-based therapeutics, has shown promise in experimental models. However, significant hurdles impede clinical translation, including poor bioavailability, off-target effects, and, most critically, the complex, context-specific biological role of SIRT1 within the liver. Ultimately, while the miRNA-SIRT1 axis appears to be a central regulatory pathway in liver disease, its translational potential and safety in humans require further mechanistic and clinical investigation.
PMID:42250161 | DOI:10.1007/s11033-026-12062-9