Hypoxia-Inducible Factors in Rheumatoid Arthritis: Central Pathogenic Roles and Therapeutic Opportunities

Rheumatoid arthritis (RA) joints are characterized by a persistently hypoxic microenvironment that drives activation of hypoxia-inducible factors (HIFs). In RA synovium, both HIF-1α and HIF-2α accumulate across key cellular compartments (fibroblast-like synoviocytes, macrophages, endothelial cells, and chondrocytes) and correlate with disease activity, positioning HIF signaling as a central node linking hypoxic stress to inflammation, metabolic rewiring, angiogenesis, and joint destruction. Notably, HIF-1α primarily regulates inflammatory responses and metabolic adaptation, whereas HIF-2α plays a more prominent role in cartilage degradation and structural joint damage, highlighting isoform-specific functions in RA pathogenesis. This review summarizes current evidence on the role of HIF in RA, focusing on its regulatory effects on immune cell function, immunometabolism, angiogenesis, and cartilage and bone destruction. We also discuss emerging therapeutic strategies targeting HIF signaling, including small-molecule inhibitors, gene-silencing approaches, and natural products. Finally, we address translational challenges, particularly isoform selectivity, local drug delivery, and biomarker-guided patient stratification. This review aims to provide an integrated perspective on the pathogenic and therapeutic roles of HIF in RA and to highlight future directions for HIF-targeted therapies.