Autophagy in Rheumatoid Arthritis: Molecular Mechanisms, Diagnostic Biomarkers, and Emerging Therapeutic Strategies

Rheumatoid arthritis (RA) is a chronic autoimmune disorder marked by persistent synovial inflammation, joint destruction, and systemic complications. Recent research has revealed the complex involvement of autophagy, a cellular degradation and recycling process, in the pathogenesis and progression of RA. This review provides a comprehensive analysis of autophagy's multifaceted roles across immune regulation, synovial hyperplasia, osteoclastogenesis, and antigen presentation. Particular attention is given to the dualistic nature of autophagy, which may exert both protective and pathogenic effects depending on the cellular context and disease stage. We explore key molecular pathways regulating autophagy, including the mTOR, AMPK, and ULK1 axes, and detail how these are modulated by cytokines and signaling molecules characteristic of the RA inflammatory milieu. Epigenetic and genetic factors, including polymorphisms in ATG and BECN1 genes, microRNA regulation, and histone modifications, are also examined for their impact on autophagic flux and immune dysregulation. The diagnostic potential of autophagy-related biomarkers is discussed through transcriptomic and bioinformatics studies that stratify RA subtypes and correlate autophagic activity with disease severity. Additionally, we review therapeutic strategies targeting autophagy, encompassing conventional DMARDs, biologics, small molecules, nanoparticles, and phytochemicals. While modulating autophagy shows clinical promise, challenges remain regarding safety, specificity, and long-term efficacy. The integration of high-throughput omics technologies with artificial intelligence presents new opportunities to refine diagnostic precision and develop personalized therapeutic interventions. This review underscores the necessity of further translational research to define context-specific roles of autophagy in RA and to harness its potential in advancing precision medicine.