Molecular mechanisms and therapeutic strategies of macrophage-fibroblast crosstalk in gouty arthritis

Gouty arthritis is an inflammatory joint disease driven by the deposition of urate crystals, with its pathological core involving innate immune activation and synovial microenvironment remodeling. Recent studies have revealed that the crosstalk between macrophages and fibroblasts plays a critical regulatory role in disease initiation, amplification of acute inflammation, and chronicity. However, the molecular network of this crosstalk and its dual role in maintaining and disrupting joint homeostasis remain insufficiently understood, and direct evidence in gouty arthritis is limited. Drawing on evidence from fibrotic diseases, rheumatoid arthritis, and other inflammatory arthropathies, this review outlines three pathways potentially mediating this crosstalk: the PRG4-CD44 immunomodulatory axis maintains joint homeostasis by regulating synovial lubrication and immune tolerance; SPP1+ matrix-remodeling macrophages drive fibroblast activation and tissue fibrosis; the mechanotransduction pathway senses mechanical microenvironment changes induced by urate crystal deposition and coordinately regulates the inflammatory response. It further delves into the potential mechanisms of these pathways in acute inflammatory flares and chronic tissue destruction, while exploring therapeutic strategies targeting these pathways, including PRG4 recombinant protein, SPP1 neutralizing antibodies, and mechanotransduction inhibitors, aiming to establish a critical framework for future validation of precision interventions in gouty arthritis.