miR-125a/b as key regulators of the pathogenesis of cholestatic liver diseases: a review of molecular mechanisms

Joanna Agnieszka Abramczyk, Agnieszka Kempińska-Podhorodecka

Abstract


MicroRNAs are small, non-coding RNA molecules that play a crucial role in the regulation of gene expression at the post-transcriptional level, influencing various physiological and pathological processes. The microRNAs miR-125a and miR-125b have divergent roles in the pathogenesis of chronic cholestatic liver diseases such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). miR-125a exerts protective effects by inhibiting the expression of pro-inflammatory cytokines (tumour necrosis factor-α, interleukin-1β), limiting transforming growth factor (TGF)-β-dependent activation of hepatic stellate cells, and reducing oxidative stress. Additionally, microR-125a supports hepatocyte regeneration, promotes the M2 macrophage phenotype, and maintains immune homeostasis. Consequently, its expression is associated with protective effects, significant therapeutic potential, and may have possible utility as a protective and prognostic biomarker. In contrast, miR-125b primarily fulfils pathological functions. Its overexpression enhances the production of pro-inflammatory cytokines, activates T lymphocytes, and potentiates TGF-β signalling – promoting fibrogenesis. It also increases hepatocyte apoptosis and oxidative stress, contributing to disease progression and the development of hepatocellular carcinoma and cholangiocarcinoma. The expression of both microRNAs is modulated by epigenetic factors and is dependent on age and sex, underscoring their significance in the personalisation of therapy for PBC and PSC. Understanding the distinct mechanisms of action of miR-125a and miR-125b can open new avenues for developing targeted therapeutic strategies that could improve prognosis and quality of life in patients with cholestatic liver diseases.

Keywords


microRNA; primary biliary cholangitis; primary sclerosing cholangitis; liver fibrosis; immune response; biomarkers

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References


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