TEAD4 integrates IFN-γ and TGF-β signaling to drive pathogenic synovial fibroblast programs in difficult-to-treat rheumatoid arthritis

Difficult-to-treat rheumatoid arthritis (D2T RA) remains a major unmet clinical challenge, with synovial fibroblasts increasingly recognized as key drivers of persistent inflammation and treatment resistance. Recent single cell and spatial transcriptomic studies have identified pathogenic fibroblast subsets, including sublining DKK3⁺, THY1 ^high , ITGA5⁺, and COMP ^high populations, associated with multidrug-resistant disease states. However, transcriptional regulators integrating inflammatory and profibrotic signaling in these fibroblast states remain poorly defined. In addition, inference-based approaches using transcriptomic data are limited in accurately capturing transcription factor activity. Here, we applied nuclear proteomics using data-independent acquisition mass spectrometry (DIA-MS) to directly identify transcription factors induced in cytokine-stimulated rheumatoid arthritis synovial fibroblasts. We identified TEAD4 as a transcription factor selectively upregulated by IFN-γ signaling. Transcriptomic and functional analyses demonstrated that TEAD4 regulates gene programs associated with multidrug-resistant fibroblast subsets and functions as a molecular bridge integrating IFN-γ-driven inflammatory signaling with TGF-β-dependent fibroblast activation. Comparative knockdown studies revealed that TEAD family members exhibit both redundant and distinct functions and partially operate independently of YAP/TAZ. Pharmacologic inhibition of TEAD activity suppressed fibroblast proliferation and migration in vitro and attenuated arthritis severity in the collagen-induced arthritis model without impairing antigen-specific immune responses. These findings identify TEAD signaling as a therapeutically targetable axis linking inflammatory and profibrotic fibroblast programs in rheumatoid arthritis.