Background Sjögren’s syndrome (SS) is a chronic systemic autoimmune disease in which CD4+ T cells play a critical role. Recent advances in immunometabolism suggest that metabolic reprogramming contributes to autoimmune pathogenesis. This study investigates the role of fatty acid synthase (FASN) in CD4+ T cell dysfunction in SS. Methods Peripheral blood CD4+ T cells were isolated from SS patients and healthy controls. FASN expression was assessed via PCR, Western blot, and immunofluorescence. Functional and metabolic assays, including flow cytometry, Seahorse analysis, transcriptomic profiling, and global metabolomics (Q300) were performed using murine and human CD4+ T cells treated with the FASN inhibitor orlistat. Rescue experiments were conducted with oleic acid (OA) and palmitoleic acid (PA). In vivo efficacy was evaluated in NOD/LtJ and experimentally-induced SS (ESS) mouse models. Results FASN was significantly upregulated in CD4+ T cells from SS patients and activated murine T cells, correlating with disease activity markers. Orlistat-mediated FASN inhibition suppressed T cell proliferation, activation (CD25/CD69), and glycolytic metabolism, while enhancing oxidative phosphorylation (OXPHOS), leading to elevated ROS and mitochondrial dysfunction. Metabolomics identified reduced OA and PA levels upon FASN inhibition. Exogenous OA and PA partially restored metabolic balance and activation markers. In murine models, orlistat reduced salivary gland lymphocytic infiltration, pro-inflammatory cytokines (IL-17/TNF-α), and improved salivary flow. Conclusion FASN drives CD4+ T cell hyperactivation and metabolic reprogramming in SS. Its inhibition shifts cell metabolism from glycolysis to OXPHOS, reducing inflammation and ameliorating disease in preclinical models. These results identify FASN as a potential therapeutic target for SS.

FASN-mediated metabolic reprogramming drives CD4⁺ T cell hyperactivation in Sjögren’s syndrome via fatty acid oxidation-dependent oxidative phosphorylation

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2026年2月13日

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Lei Ye,
Xijun Wang,
Junhao Yin,
Huan Shi,
Jiayao Fu,
Baoli Wang,
Lingyan Zheng

摘要

Background

Sjögren’s syndrome (SS) is a chronic systemic autoimmune disease in which CD4⁺ T cells play a critical role. Recent advances in immunometabolism suggest that metabolic reprogramming contributes to autoimmune pathogenesis. This study investigates the role of fatty acid synthase (FASN) in CD4⁺ T cell dysfunction in SS.

Methods

Peripheral blood CD4⁺ T cells were isolated from SS patients and healthy controls. FASN expression was assessed via PCR, Western blot, and immunofluorescence. Functional and metabolic assays, including flow cytometry, Seahorse analysis, transcriptomic profiling, and global metabolomics (Q300) were performed using murine and human CD4⁺ T cells treated with the FASN inhibitor orlistat. Rescue experiments were conducted with oleic acid (OA) and palmitoleic acid (PA). In vivo efficacy was evaluated in NOD/LtJ and experimentally-induced SS (ESS) mouse models.

Results

FASN was significantly upregulated in CD4⁺ T cells from SS patients and activated murine T cells, correlating with disease activity markers. Orlistat-mediated FASN inhibition suppressed T cell proliferation, activation (CD25/CD69), and glycolytic metabolism, while enhancing oxidative phosphorylation (OXPHOS), leading to elevated ROS and mitochondrial dysfunction. Metabolomics identified reduced OA and PA levels upon FASN inhibition. Exogenous OA and PA partially restored metabolic balance and activation markers. In murine models, orlistat reduced salivary gland lymphocytic infiltration, pro-inflammatory cytokines (IL-17/TNF-α), and improved salivary flow.

Conclusion

FASN drives CD4⁺ T cell hyperactivation and metabolic reprogramming in SS. Its inhibition shifts cell metabolism from glycolysis to OXPHOS, reducing inflammation and ameliorating disease in preclinical models. These results identify FASN as a potential therapeutic target for SS.

FASN-mediated metabolic reprogramming drives CD4+ T cell hyperactivation in Sjögren’s syndrome via fatty acid oxidation-dependent oxidative phosphorylation

摘要

FASN-mediated metabolic reprogramming drives CD4⁺ T cell hyperactivation in Sjögren’s syndrome via fatty acid oxidation-dependent oxidative phosphorylation