Integrative transcriptomic analysis reveals miR-26a-5p downregulation and a potential predictive gene signature for...

Metabolic dysfunction-associated steatotic liver disease (MASLD) is an important inducer of hepatocellular carcinoma (HCC). MicroRNAs are key regulators of tumorigenesis. Among these, miR-26a-5p is known to be associated with liver pathogenesis, yet its role in linking MASLD progression to HCC development remains incompletely understood.

Hepatic miR-26a-5p expression was quantified in the C57BL/6 mice with a 3-month high-carbohydrate diet (HCD). Public transcriptomic datasets with MASLD and HCC samples were analyzed to identify predicted miR-26a-5p downstream candidates upregulated in the above-mentioned diseases. Associations with tumor features were examined, and protein expression of β-catenin, c-MYC and EpCAM were evaluated after miR-26a-5p modulation.

Integrative bioinformatics identified miR-26a-5p as a candidate prognostic indicator for metabolic liver disease progression. In vivo, results confirmed that suppressed miR-26a-5p expression is a hallmark of diet-induced metabolic perturbation. Mechanistically, in vitro modulation of miR-26a-5p attenuated oncogenic signaling via the β-catenin/c-Myc/EpCAM axis, establishing its role as a tumor suppressor. Notably, in silico analysis of HCC tissues revealed that high miR-26a-5p levels correlate with enhanced antitumor immunity. Leveraging these insights, we constructed a transcriptional signature from miR-26a-5p downstream candidates and MASLD-HCC differentially expressed genes. This signature effectively stratifies MASLDpatients, discriminating molecular risk groups associated with progression to HCC.

Integrating transcriptomic, clinical and experimental data suggests the role of miR-26a-5p, along with the MASLD-HCC gene signature (EpCAM, DTNA, and KPNA2), may serve as an early molecular indicator and mechanistic modulator of hepatocarcinogenesis, warranting further functional investigation.