CUL4A promotes glycolytic metabolism of fibroblast-like synoviocytes by targeting FGF2 in rheumatoid arthritis

Description

The central role in the pathogenesis of rheumatoid arthritis (RA) is played by fibroblast-like synoviocytes (FLS), which drive disease progression through aberrant proliferation, recruitment of inflammatory cells, and subsequent degradation of cartilage and bone. Cullin 4A (CUL4A) is an important member of the Cullin family, which is a scaffolding protein for the E3 ubiquitin ligase complex. In this study, we investigated the functional significance and molecular mechanisms of CUL4A in the pathogenesis of RA. We identified elevated CUL4A expression in synovial tissues, TNFα-stimulated FLS, and peripheral blood mononuclear cells from RA patients. Furthermore, CUL4A mRNA expression levels showed a positive correlation with both clinical disease activity and inflammatory markers in RA. Knockdown of CUL4A led to a marked suppression of both cytokine production and glycolytic metabolism in FLS in vitro. RNA sequencing analysis and validation revealed the PI3K/AKT pathway as a key mediator in this process, with a significant functional interaction between CUL4A and fibroblast growth factor 2 (FGF2). Furthermore, knocking down FGF2 significantly inhibited synovial inflammation in RA FLS. In vivo experiments, knocking down CUL4A significantly reduced synovial inflammation in K/BxN serum transfer-induced arthritis (STA) mice and inhibited glycolytic metabolism. In conclusion, our findings reveal that CUL4A, via FGF2 binding, initiates PI3K/AKT pathway signaling, fostering the glycolysis process and synovial inflammation. Consequently, CUL4A holds significant promise as a target for early intervention against this pathogenic cascade.

Institutions

• First Affiliated Hospital of Anhui Medical University

  Anhui, Hefei
• Anhui Medical University

  Anhui, Hefei

Categories

Funders

• the Project for Excellent Young in Colleges and Universities of Anhui Province

  Grant ID: 2023AH030120
• the Postgraduate Innovation Research and Practice Program of Anhui Medical University

  Grant ID: YJS20240063
• Inflammation and Immune Mediated Diseases Laboratory of Anhui Province

  Grant ID: IMMDL202102
• the Postgraduate Innovation Research and Practice Program of Anhui Medical University

  Grant ID: YJS20240065
• Key Projects of the Anhui Provincial University Scientific Research Program

  Grant ID: 2025AHGXZK31569
• College Students' Innovative Entrepreneurial Training Plan Program

  Grant ID: 202513618016

Licence