Dysfunctional glycolysis-UCP2-fatty acid oxidation promotes CTLA4(int)FOXP3(int) regulatory T-cell production in rheumatoid arthritis.

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 CD25(int)CTLA4(int)FOXP3(int)CD4(high) 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.