Mechanistic Landscape and Therapeutic Opportunities of Non-Coding RNAs in Modulating Fibroblast-Like Synoviocytes in Rheumatoid Arthritis.

Current disease-modifying antirheumatic drugs (DMARDs) for rheumatoid arthritis (RA) predominantly target systemic immune-inflammatory pathways, yet fail to effectively reverse progressive articular structural damage driven by fibroblast-like synoviocytes (FLS), representing a core unmet clinical need in the field. Non-coding RNAs (ncRNAs) are key epigenetic regulators of pathological FLS activation; however, the field is constrained by three core limitations: fragmented evidence, mechanistic homogenization, and a persistent basic-to-clinical translational gap. Adopting a structured evidence-grading narrative review framework, we systematically synthesize evidence on the regulatory roles of three major ncRNA classes (microRNAs [miRNAs], long ncRNAs [lncRNAs], and circular RNAs [circRNAs]) across four hallmark RA-FLS pathophenotypes: proliferation-apoptosis dysregulation, invasive matrix degradation, pro-inflammatory secretion, and metabolic reprogramming, acting via diverse mechanisms including competitive endogenous RNA (ceRNA) sponging and epigenetic modification. We further integrated a panoramic cross-class synergistic ceRNA regulatory network and identified 12 high-confidence translational targets (prioritized by clinical, in vivo, and primary cell multi-level evidence, exemplified by miR-124, miR-146a, GAS5, and circFBXW7). We also synthesize current evidence on ncRNA biomarker utility, two canonical interventional paradigms (gain-of-function [GoF] and loss-of-function [LoF] strategies), and shared translational bottlenecks across the field. Collectively, ncRNA-targeted stroma-directed therapy emerges as a novel interventional paradigm for RA articular structural protection. Prioritized future directions include FLS subpopulation-specific functional characterization, optimization of synovial-targeted delivery systems, exploration of non-canonical regulatory mechanisms, and multicenter validation of ncRNA-based biomarkers to accelerate clinical translation.