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Introduction Systemic sclerosis (SSc) is an autoimmune rheumatic and musculoskeletal disease (RMD) with high mortality. Epigenetic factors, such as miRNAs might play an important role in the pathogenesis of SSc. miRNAs are negative regulators of gene expression, thus they contribute to most biological processes.Material and Methods In this cross-sectional study we assessed altered miRNA and mRNA network in SSc and associated with disease-related biological processes.We investigated the altered miRNA profiles and differentially expressed mRNA levels of 52 SSc patients (42 women and 10 men; mean age: 59.1 years (range: 33-76 years)). Anticoagulated blood samples were taken from SSc patients, as well as age- and gender-matched healthy controls. Peripheral blood mononuclear cells (PBMC) were isolated on a Ficoll gradient, stored in TRIzol at -20°C until use. Total RNA purified. Sequencing of miRNAs and mRNAs were performed using high-throughput, new generation (Illumina) sequencing, and established miRNA and mRNA library.Results Altogether 58 miRNAs showed significantly differential expression in SSc patients compared to controls. Among these miRNAs, 34 were significantly upregulated and 24 downregulated. Evaluating the same samples, we found 6610 differentially expressed mRNAs(Mann-Whitney unpaired test,p<0,05). 31 genes remained significantly upregulated and 9 genes significantly downregulated after Benjamini-Hochberg FDR multiple testing correction. We found 180 validated, inverse connections between the differentially expressed miRNAs and mRNAs using miRTarBase and TarBase databases ( figure 1). Gene Ontology(GO) enrichment analysis suggested connection between the overactivated genes and biological processes of the negative regulation of peptidase activities (adjusted p<0,05). The four most frequent genes involved in the detected biological processes are EGR1, MMP9, PLEC and NR4A1. EGR1 is a central transcription factor that promotes fibrotic gene expression, such as collagen and fibronectin. Elevated levels of MMP9 have been reported to correlate with the degree of skin involvement of SSc patients. PLEC gene encodes plectin, a giant multifunctional cytolinker protein, playing crucial role in orchestrating intermediate filament networks, however its connection with SSc have not been described yet. NR4A1 is a gene of Nuclear Receptor Subfamily 4A, which have been signified as a key pathway of cell dysregulation in SSc, according to the literature.Conclusions SSc is associated with the differential expression of several genes might be induced by altered miRNA patterns. Evaluating the significantly overexpressed genes, we revealed several biological processes associated with fibrosis. The main genes participating in these molecular processes might be important in the pathogenesis of SSc, and they might serve as therapeutic targets as well.Grant support: GINOP-2.3.2-15-2016-00015Abstract P.030 Figure 1Differentially expressed miRNA-mRNA network. Coloured based on logFC data (red: significantly upregulated, blue: significantly downregulated)