Non-Coding RNA Networks in Systemic Sclerosis: Roles in Pathogenesis, Biomarkers, and Therapeutic Opportunities

Non-coding RNAs have emerged as gene-regulatory molecules acting at epigenetic, transcriptional, and post-transcriptional levels. Among them, microRNAs are short RNA molecules consisting of approximately 22 nucleotides. Increased microRNA expression suppresses target protein expression, whereas decreased microRNA expression relieves this repression and can induce overexpression of target proteins. microRNAs integratively regulate highly complex biological processes, including cell proliferation, differentiation, apoptosis, morphogenesis, and immune responses. Therefore, alterations in microRNA expression profiles may be directly linked to the fundamental pathogenesis of systemic sclerosis (SSc), an autoimmune and fibrotic disease involving multiple organs. This focused narrative review examines microRNAs involved in SSc fibrosis, vasculopathy, and immune dysregulation; extracellular-particle-associated microRNAs; and circulating and hair-derived microRNAs as candidate biomarkers. It also summarizes evidence on long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), yRNAs, and PIWI-interacting RNAs (piRNAs). Finally, therapeutic perspectives, including microRNA mimics, antisense inhibitors, and broader RNA-targeted strategies, are discussed together with key challenges in validation and clinical translation.