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Introduction: Juvenile idiopathic arthritis (JIA) is a chronic inflammatory joint disorder affecting children, in which T cells function within a microenvironment characterized by low glucose and elevated fatty acid levels. The metabolic mechanisms that allow T cells to adapt and remain active under these nutrient-limited conditions are still not well understood.

Methods: We examined T cells from both the peripheral blood (PB) and Synovial fluid (SF) of JIA patients and conducted bulk gene expression analysis and single-cell RNA sequencing. These analyses revealed increased expression of Fatty Acid Transport Protein 2 (FATP2), which was confirmed by flow cytometry. We then investigated the effects of inhibiting FATP2 using the compound lipofermata in vitro through flow cytometry and RNA sequencing and in vivo using a collagen-induced arthritis mouse model.

Results: T cells from SF showed significantly higher fatty acid uptake and FATP2 expression compared to PB T cells, particularly in activated and memory T cell subsets. Inhibition of FATP2 with lipofermata reduced fatty acid uptake, T cell proliferation, and interferon-γ production through pAKT3/mTOR-dependent pathway. However, lipofermata treatment did not alleviate arthritis symptoms in mice, likely because FATP2 is not similarly regulated in mouse memory T cells. Analysis of open-source sequencing data indicates FATP2 is also upregulated in psoriatic and rheumatoid arthritis at sites of inflammation. A humanized psoriatic arthritis mouse model is planned.

Conclusion: These findings indicate that T cells in JIA adapt to a fatty acid–rich environment by increasing FATP2 expression. Disrupting this metabolic adaptation through FATP2 inhibition may represent a potential therapeutic strategy for treating JIA and other autoimmune inflammatory diseases.