Mechanistic Landscape and Therapeutic Opportunities of Non‐Coding
RNAs
in Modulating Fibroblast‐Like Synoviocytes in Rheumatoid Arthritis
Lei Chen, Fengping Wang ABSTRACT
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.