FGF/FGFR signaling at the immune-stromal interface in autoimmune rheumatic diseases: from tissue remodeling to translational opportunities.

The fibroblast growth factor (FGF)/FGF receptor (FGFR) signaling system regulates tissue repair, angiogenesis, extracellular matrix remodeling, fibrosis, and bone metabolism. Although FGF/FGFR biology has been extensively studied in oncology, development, and fibrotic lung disease, its relevance to systemic autoimmune rheumatic diseases remains scattered across disease-specific and unevenly supported literatures. This narrative, evidence-informed review synthesizes current evidence on FGF/FGFR signaling in rheumatoid arthritis (RA), systemic lupus erythematosus/lupus nephritis (SLE/LN), systemic sclerosis (SSc), spondyloarthritis/psoriatic arthritis (SpA/PsA), and Sjögren's disease. We explicitly distinguish mechanistically supported axes from biomarker-level associations and extrapolated regenerative concepts. In RA, FGF10/FGFR1 and FGF2/FGFR3 have the strongest tissue-level support, linking relapse-prone synovial fibroblast niches, fibroblast-like synoviocyte activation, angiogenesis, and bone erosion. In SLE/LN, FGF23/Klotho is best interpreted as an emerging renal-metabolic and inflammatory biomarker axis rather than a validated therapeutic target, although reported associations with urinary MCP-1/CCL2 suggest testable links to renal chemokine-mediated inflammation. In SSc-ILD, nintedanib demonstrates that FGFR-containing multi-kinase networks are clinically tractable, but the FGFR-specific contribution remains unresolved. In SpA/PsA, FGF2-mediated angiogenesis-osteogenesis coupling and FGF7/FGFR2IIIb signaling provide candidate mechanisms for entheseal remodeling, whereas direct human entheseal validation is still lacking. In Sjögren's disease, FGF7/FGF10/FGFR2b signaling supports a regenerative hypothesis derived mainly from salivary gland developmental biology and organoid studies. We propose an axis-prioritization translational framework that specifies ligand-receptor pairs, patient subgroups, validation tissues, delivery strategies, pharmacodynamic endpoints, and clinical or imaging readouts. This review is not a systematic review or meta-analysis; rather, it provides a structured roadmap for tissue-level validation, longitudinal biomarker studies, and short-course proof-of-mechanism trials before clinical translation.