TFRC-associated ferroptosis in synovial macrophages promotes inflammatory and fibrotic remodeling in osteoarthritis.

Osteoarthritis (OA) is a degenerative joint disease; however, the role of ferroptosis in synovial macrophages remains poorly defined. Here, we integrated single-cell RNA sequencing data from human synovial tissues to systematically characterize cellular heterogeneity and ferroptosis-associated alterations. Nine major cell types were identified, among which synovial macrophages exhibited the highest ferroptosis scores, significantly elevated in OA compared with normal controls. Macrophages with high ferroptosis scores showed pronounced upregulation of genes associated with inflammation, extracellular matrix remodeling, and lipid metabolism, indicating a coordinated state of metabolic reprogramming and inflammatory activation. Using an ensemble machine learning framework, we identified and validated key ferroptosis-related genes, including TFRC, GCLC, GSS, and TP53. Notably, TFRC demonstrated superior specificity and sensitivity and was strongly correlated with ferroptosis activity. Cell-cell communication analysis further revealed that ferroptosis-high macrophages function as central signaling hubs, transmitting TNF- and TGFβ-mediated signals to stromal and vascular cells, thereby promoting synovial inflammation, fibrosis, and angiogenesis. Collectively, our findings identify TFRC as a candidate ferroptosis-associated marker in synovial macrophages and suggest that ferroptosis-associated changes are linked to pro-inflammatory polarization and pathogenic intercellular communication in OA. These findings provide insights into the potential involvement of ferroptosis in synovial macrophage dysfunction and highlight ferroptosis-related pathways as potential therapeutic targets for further investigation.