Dysfunctional glycolysis-UCP2-fatty acid oxidation promotes CTLA4intFOXP3int regulatory T-cell production in rheumatoid arthritis

  • Mol Med. 2025 Oct 9;31(1):310. doi: 10.1186/s10020-025-01372-6.
Jiawen Han  #  1 ,  Zhongyang Zhou  #  1 ,  Hongxia Wang  #  2  3 ,  Yuxin Chen  #  4 ,  Wuguo Li  1 ,  Meiqin Dai  1 ,  Jing Bian  1 ,  Erming Zhao  1 ,  Jiaying He  1 ,  Xinyao Zhang  5 ,  Huanfa Yi  6 ,  Lan Shao  7
Affiliations
  • 1. The Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, P. R. of China.
  • 2. Laboratory Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, P.R. of China.
  • 3. Department of Rheumatology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, P. R. of China.
  • 4. Department of Laboratory Medicine, Affiliated Hospital of Medical School, Nanjing Drum Tower Hospital, Nanjing University, Nanjing, 210008, P. R. of China.
  • 5. Department of Urology, Henan Cancer Hospital, Zhengzhou, 450008, P.R. of China.
  • 6. Central Laboratory, The First Hospital of Jilin University, Changchun, 130061, P.R. of China.
  • 7. The Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, P. R. of China. [email protected].
  • # Contributed equally.
PMID: 41068616 DOI: 10.1186/s10020-025-01372-6
Abstract

In rheumatoid arthritis (RA), the impaired function of regulatory T cells (Tregs) induces chronic inflammatory responses in the synovium. Cytotoxic T Lymphocyte Antigen 4 (CTLA4) is crucial for Sustaining Treg function. Uncoupling Protein 2 (UCP2) plays a key role in linking the glycolysis and fatty acid oxidation (FAO) pathways. Here we observed that Tregs in RA were predominantly characterized by a CD25intCTLA4intFOXP3intCD4high Phenotype. Mechanistically, elevated expression of UCP2 in RA Tregs disrupted metabolic homeostasis by downregulating Carnitine Palmitoyltransferase 2 (CPT2), a rate-limiting enzyme in the FAO pathway. Impaired FAO trigged caveolae-mediated endocytosis, leading to reduced CTLA4 cell surface accumulation and diminished Treg suppressive capacity. Moreover, UCP2 inhibition attenuated the pro-inflammatory effects of RA T cells in a human-SCID chimeric mouse model. Our results establish a critical link between CTLA4 endocytosis and UCP2-mediated metabolic shift in Tregs and identified UCP2 as a potential therapeutic target for preventing RA autoimmunity.

Supplementary Information: The online version contains supplementary material available at 10.1186/s10020-025-01372-6.

Keywords
CTLA4; Caveolae; Fatty acid β-oxidation; Glycolysis; Rheumatoid arthritis; Treg; UCP2.
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