Drug repurposing in hepatocellular carcinoma through mirRNA-gene drug interaction and clinical survival correlation

Sammanfattning

Hepatocellular carcinoma (HCC) is a major global health challenge with limited therapeutic options for advanced disease. miRNAs are small non-coding RNAs that are frequently dysregulated in HCC and directly influence post-transcriptional gene regulation. This study adapted the miRFA bioinformatics pipeline to integrate paired miRNA and mRNA expression data from TCGA-LIHC (n = 368 matched patients) for the systematic identification of candidate repurposable drugs in HCC. Differential expression analysis using edgeR identified 173 dysregulated miRNAs and 5,101 dysregulated mRNA transcripts in tumour tissue relative to normal liver controls (FDR < 0.05, |log₂FC| > 1). Experimentally validated miRNA–mRNA interactions were retrieved via multiMiR and filtered by Pearson correlation across the matched cohort, yielding 24 candidate regulatory pairs (r = −0.151 to −0.215) distributed across three hub miRNAs that captured bidirectional dysregulation: hsa-mir-7706 and hsa-mir-1269 awere upregulated in tumour tissue, whereas hsa-mir-1258 was downregulated. KEGG pathwayenrichment of the 24 target genes identified Parathyroid hormone synthesis, secretion and action(hsa04928) as the single pathway surviving Benjamini–Hochberg correction (adjusted p = 0.02), driven by SGK1, EGR1, and MEF2C. Kaplan–Meier survival analysis of MT-ND5, the gene most strongly negatively correlated with its hub miRNA, did not reach statistical significance (log-rank p = 0.12). Insilico drug repurposing against the LINCS L1000 chemical perturbation database revealed strong mechanistic convergence among the top ten candidates on the PI3K/AKT/mTOR signalling axis (six often compounds), with the pan-HDAC inhibitor pracinostat as the second-ranked compound. This work provides a reproducible computational framework for transcript omics-based drug repurposing in HCCand identifies a set of candidate miRNA–mRNA pairs and compounds for future experimental investigation.