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Nuclear proteomics identifies TEAD4 as an IFN-γ-responsive regulator of pathogenic synovial fibroblast programs

Year: 2026

Type: preprint

Abstract: Difficult-to-treat rheumatoid arthritis (D2T RA) remains a major unmet clinical challenge despite advances in targeted therapies. Recent single-cell and spatial transcriptomic studies identified synovial fibroblast (SF) subsets associated with multidrug-resistant disease states. Transcriptome-based inference approaches have been used to further characterize pathogenic fibroblast subsets by identifying candidate master transcriptional regulators. However, their accuracy is limited by the context-dependent relationship between transcription factors and their target genes. Here, we applied nuclear proteomics using data-independent acquisition mass spectrometry (DIA-MS) to identify transcription factors regulated in cytokine-stimulated rheumatoid arthritis synovial fibroblasts (RASFs). Nuclear DIA-MS identified TEAD4 as a transcription factor selectively induced by IFN-γ signaling. Transcriptomic and functional analyses demonstrated that TEAD4 regulates gene programs associated with multidrug-resistant fibroblast subsets, including TGF-β-associated fibroblast activation programs. Comparative perturbation analyses showed that TEAD family members exhibit both redundant and distinct functions and regulate transcriptional programs that only partially overlap with those controlled by 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. Together, these findings identify TEAD signaling as a therapeutically targetable pathway in rheumatoid arthritis and provide a mechanistic framework linking inflammatory and profibrotic fibroblast activation.

Source: Research Square

DOI: 10.21203/rs.3.rs-11191053/v1

Authors: Tetsuya Saito, Motohiko Sato, Kenta Horie, Takahiro Nakahara, Rihan Da, Shiyao Li, Akio Yamamoto, Seiji Noda, Tadashi Hosoya, Yasuhiro Takahara, Kazutaka Sugimoto, Kentaro Endo, Hideyuki Koga, Ichiro Sekiya, Eiryo Kawakami, Shinsuke Yasuda

Institutions: Institute of Science Tokyo, Tokyo Medical and Dental University, Chiba University

Language: English

Topic: Rheumatoid Arthritis Research and Therapies

Subfield: Rheumatology

Field: Medicine

Domain: Health Sciences

Open Access status: green

OpenAlex ID: W7225734745

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