TWIST1 ‐Mediated Induction of AEBP1 in Fibroblast‐Like Synoviocytes Activates Transforming Growth Factor β Signaling to Drive Angiogenesis and Promote Rheumatoid Arthritis

Objective Aggressive fibroblast‐like synoviocytes (FLS) drive synovial hyperplasia, extracellular matrix (ECM) remodeling, and pannus formation in rheumatoid arthritis (RA). However, the pathogenic FLS subpopulations and their upstream regulators remain incompletely defined. This study aimed to (i) identify FLS subpopulation(s) responsible for synovial hyperplasia, ECM remodeling, and pannus development, (ii) elucidate the molecular mechanisms regulating their pathogenic activation, and (iii) explore therapeutic strategies targeting FLS activation and pannus‐associated neovascularization in RA. Methods We integrated bulk RNA sequencing, proteomics, and single‐cell transcriptomics to identify pathogenic FLS subpopulation(s) in RA synovium. Functional assays were conducted to assess the effects of adipocyte enhancer‐binding protein 1 (AEBP1) and periostin (POSTN) expression on FLS activation, ECM remodeling, and angiogenesis. Bioinformatic analyses and cell biologic experiments were adopted to identify the upstream regulator responsible for AEBP1 expression in FLS. We subsequently investigated the pathologic impact of TWIST1–AEBP1–POSTN axis in a collagen‐induced arthritis (CIA) mice model. Results We identified a pathogenic POSTN + FLS subgroup selectively enriched within the sublining layer of synovium that exhibited robust ECM remodeling and fibrogenic features. Mechanistically, we showed that AEBP1 was selectively elevated in these cells, in which it activated transforming growth factor β signaling to drive fibroblast activation, migration, and proliferation. Besides, AEBP1 also induced POSTN expression, which was responsible for neovascularization. Further, inflammatory signalings induced TWIST1 expression, which directly regulated AEBP1 transcription in FLS. Intra‐articular modulation of AEBP1 in mice with CIA had opposite effects on synovial hyperplasia, bone erosion, and pannus formation. Moreover, the pharmacological inhibition of TWIST1 by harmine‐reduced AEBP1 and POSTN expression, limited the expansion of pathogenic THY1 + FLS, and alleviated joint pathology. Conclusion Our study suggests that POSTN + FLS located in the synovial sublining contribute to RA progression through the TWIST1–AEBP1–POSTN axis. Accordingly, targeting of this axis may offer a novel and effective approach for RA treatment. image