Pigmented villonodular synovitis (PVNS), or tenosynovial giant cell tumor (TGCT), is a locally aggressive soft tissue tumor primarily affecting the synovium of joints, particularly the knee. In PVNS, the synovial tissue thickens and becomes aggressive, leading to joint destruction, a process reminiscent of the tissue remodeling seen in autoimmune diseases. Despite being considered benign, PVNS often leads to severe joint damage and has a high recurrence rate following treatment. The underlying molecular mechanisms of PVNS remain poorly understood, necessitating further research to uncover its pathogenesis and identify potential therapeutic targets. This study aims to investigate the pathological mechanisms of PVNS, focusing on the role of metabolic pathways, immune cell infiltration, and osteoclast differentiation in the progression of the disease.Synovial fluid samples from PVNS patients were subjected to high-throughput proteomic and metabolomic analyses. Differentially expressed proteins (DEPs) and metabolites were identified, and pathway enrichment analysis was performed. Western blot validation and two-way orthogonal partial least squares (O2PLS) analysis confirmed key findings and explored the relationships among identified biomarkers.A total of 156 DEPs and 62 differential metabolites were identified. The "Osteoclast differentiation signalling" and "Nuclear factor-κB (NF-κB) survival signalling" pathways were significantly upregulated in PVNS samples, with Tumor Necrosis Factor Superfamily Member 11 (TNFSF11), Cathepsin K (CTSK), Adhesion G Protein-Coupled Receptor E5 (ADGRE5), and NF-κB showing marked increases in expression. Metabolomic analysis revealed that "Linoleic acid metabolism" and "Biosynthesis of unsaturated fatty acids" pathways were enhanced in PVNS, with metabolites such as 13-L-Hydroperoxylinoleic acid and 13-OxoODE being highly expressed. Western blot validation confirmed the elevated levels of ADGRE5, TNFSF11, CTSK, and NF-κB, suggesting a link between enhanced energy metabolism, lipid oxidation, and osteoclast differentiation.  CONCLUSIONS: This study highlights the critical role of metabolic adaptations and immune cell activity in the progression of PVNS. The findings suggest that targeting ADGRE5 and NF-κB could offer new therapeutic strategies for controlling disease progression and reducing joint destruction in PVNS patients. Further research is needed to elucidate this disease's specific regulatory mechanisms and cell types.© 2025. The Author(s).