ACSL5 programs fatty acid metabolism and mitochondrial fitness to sustain pathogenic T cells and exacerbate Sjögren's syndrome.

Emerging evidence has shown that fatty acid metabolism is closely associated with autoreactive T cells in autoimmunity, but its function in Sjögren's syndrome (SS) is still unclear. Here, we identified acyl-CoA synthetase long-chain family member 5 (ACSL5) as a metabolic checkpoint that drives pathogenic T-cell responses in SS. ACSL5 was upregulated in patients with SS and positively correlated with T-cell infiltration and lipid dysregulation. ACSL5-high T cells presented hyperactive effector activity and a proinflammatory phenotype. Metabolic profiling indicated that ACSL5 increased fatty acid uptake and utilization and promoted fatty acid oxidation (FAO) through peroxisome proliferator-activated receptor alpha (PPARα) in T cells, thereby improving mitochondrial respiratory capacity. Mechanistically, ACSL5 facilitated the nuclear translocation of PPARα and subsequent Mitofusin 2 (MFN2) transcription, increasing mitochondrial elongation and the formation of mitochondria‒endoplasmic reticulum contacts (MERCs) to influence the FAO and T-cell response. Disruption of the ACSL5/PPARα/MFN2 axis attenuated effector functions and reduced the longevity of pathogenic effector T cells. Pharmacological inhibition of FAO or ACSL5 decreased inflammatory T-cell infiltration and alleviated salivary gland inflammation. Collectively, these findings reveal an ACSL5-centered metabolic program that sustains pathogenic T-cell responses in SS and suggest ACSL5/FAO as a potential therapeutic target.