2. Academic Validation
  3. CUL4A promotes glycolytic metabolism of fibroblast-like synoviocytes by targeting FGF2 in rheumatoid arthritis

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

  • Biochem Pharmacol. 2026 May:247:117783. doi: 10.1016/j.bcp.2026.117783.
Dantong Sun 1,  Jun Wang 2,  Xue Yang 3,  Han Shu 3,  Yongfeng Cheng 4,  Ying Chen 3,  Qingqing Xia 5,  Facai Wang 5,  Siwei Deng 4,  Jun Li 6,  Xiao-Feng Li 7,  Biao Song 8
Affiliations

Affiliations

  • 1 Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, School of Pharmacy, Anhui Medical University, Hefei 230032, China.
  • 2 Department of Orthopedics, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.
  • 3 Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, School of Pharmacy, Anhui Medical University, Hefei 230032, China.
  • 4 Clinical College of Anhui Medical University, Hefei 230031, China.
  • 5 Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, School of Pharmacy, Anhui Medical University, Hefei 230032, China; Department of Pharmacy, Lu'an Hospital of Anhui Medical University, Lu'an People's Hospital of Anhui Province, Lu'an 237006, China.
  • 6 Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, School of Pharmacy, Anhui Medical University, Hefei 230032, China. Electronic address: [email protected].
  • 7 Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, School of Pharmacy, Anhui Medical University, Hefei 230032, China; Department of Orthopedics, the Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China. Electronic address: [email protected].
  • 8 Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, School of Pharmacy, Anhui Medical University, Hefei 230032, China; Clinical College of Anhui Medical University, Hefei 230031, China. Electronic address: [email protected].
PMID: 41679658 DOI: 10.1016/j.bcp.2026.117783
Abstract

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.

Keywords

CUL4A; Fibroblast-like synoviocytes; K/BxN serum transfer-induced arthritis; Rheumatoid arthritis; Synovial inflammation.

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