Fibroblast Iron Metabolic Reprogramming Links Chronic Inflammation to Extracellular Matrix Remodeling and Pathological Ossification

Joints and their associated ligamentous structures constitute a dynamic interface for immune–stromal interactions, and chronic inflammatory joint diseases are marked by a paradoxical coexistence of persistent inflammation and progressive structural remodeling, including fibrosis and ectopic bone formation. Using radiographic axial spondyloarthritis (r-axSpA) as a disease model, we identify fibroblasts as key tissue-level organizers of inflammation-driven joint remodeling through dysregulated iron metabolism. Integrating single-cell transcriptomic analyses of patient tissues with genetic and functional studies in multiple experimental models, we show that among diverse stromal and immune populations within inflamed joints, ligament and tendon fibroblasts uniquely accumulate iron and engage extracellular matrix (ECM) remodeling programs. Mechanistically, inflammatory signaling—most prominently tumor necrosis factor α (TNFα)—reprograms fibroblast iron handling by sustaining expression of the iron transporter SLC39A14, thereby enabling persistent iron influx. Iron-loaded fibroblasts drive excessive ECM deposition, reshape stromal–immune crosstalk, and generate a tissue microenvironment permissive for pathological ossification. In vivo, fibroblast-specific disruption of this pathway attenuates iron accumulation, fibrotic remodeling, and aberrant bone formation, while ECM deposited by iron- and inflammation-reprogrammed fibroblasts is sufficient to instruct osteogenic differentiation of mesenchymal progenitors. Together, these findings identify fibroblast-mediated iron handling as a tissue-level control mechanism that links chronic inflammation to joint remodeling and ossification, providing a generalizable framework for structural pathology in inflammatory diseases.