Integrated Transcriptome and Metabolomics Analyses Show MYC as a Potential Therapeutic Target for Behçet's Uveitis.

Abstract

Behçet's uveitis (BU), characterized by recurrent bilateral panuveitis, is a severe manifestation of Behcet's disease (BD). However, disease-specific metabolic alterations in BU remain largely unknown. Here, untargeted metabolomics and single-cell RNA sequencing (scRNA-seq) are performed in patients with BU and healthy controls (HC). scRNA-seq data of experimental autoimmune uveitis (EAU) mice are also incorporated. The data showed an altered metabolic profile, characterized by upregulated glycolysis in BU. MYC is predicted to be a hub molecule regulating glycolysis and T cell response. Notably, it is discovered that the expression level of MYC is higher in BU compare to HC and may reflect the treatment response of BU disease. Correspondingly, the scRNA-seq data of EAU mice also reveal higher glycolysis levels and MYC expression. Further studies reveal that inhibition of MYC repressed glycolysis and exerted therapeutic effects similar to those of glycolysis inhibitors, including amelioration of EAU and repression of the abnormal response of effector T cells (T helper [Th]-1 and Th17 cells). Mechanically, inhibiting MYC disrupts the glycolysis-PI3K signaling circuit to curb the effector T cell response in uveitis. Collectively, the study indicated that MYC promoted glycolysis to fuel abnormal T-cell responses, thus therapeutically targeting MYC would provide an attractive approach for treating BU.