Dysregulation of miRNAs in Sicilian Patients with Huntington’s Disease

<b>Background/Objectives</b>: Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG nucleotide repeat expansion in the Huntingtin (<i>HTT</i>) gene. Dysregulation of microRNAs (miRNAs), key post-transcriptional regulators of gene expression, has been implicated in HD pathogenesis, although their specific roles remain incompletely understood. <b>Methods</b>: Peripheral blood mononuclear cells from Sicilian HD patients and matched healthy controls were subjected to small RNA sequencing. Differential expression analysis was conducted using DESeq2 (version 1.44.0), with significance defined as |fold change| ≥ 1.5 and adjusted <i>p</i> ≤ 0.05. Ingenuity Pathway Analysis (IPA) was applied to assess functional enrichment, focusing on neurological diseases, inflammatory processes, and miRNA-RNA messenger (mRNA) interaction networks. <b>Results</b>: A total of 790 differentially expressed miRNAs were identified in HD patients (270 upregulated and 520 downregulated). IPA revealed enrichment in pathways related to organismal injury, neurological disease, and inflammatory responses. Four major regulatory networks linked differentially expressed miRNAs to neurodegenerative processes, with target genes involved in neuroinflammation, cellular stress responses, and metabolic dysfunction. Cross-referencing with previous RNA-seq data identified 5721 high-confidence miRNA-mRNA interactions, implicating 721 target genes across 54 key canonical pathways. <b>Conclusions</b>: HD patients exhibit a distinct and reproducible peripheral blood miRNA expression signature. These dysregulated miRNAs may represent accessible biomarkers and provide mechanistic insights into HD pathogenesis, with potential applications for diagnosis, prognosis, and therapeutic development.