Lipid-sensing GPR183-KRAS signaling mediates T(H)17 autoimmunity and identifies fluvoxamine repurposing in uveitis.

GPR183 activation in pathogenic CD4+ T cells promotes TH17 pathogenicity via KRAS signaling, linking copper overload–induced mitochondrial oxidative stress to metabolic rewiring toward glycolysis.

• Why it matters: Autoimmune uveitis is driven by TH17 inflammation, but immunometabolic mechanisms and actionable targets remain poorly defined, limiting effective therapies.
• What they did: Using single-cell RNA sequencing and multilayered metabolomic profiling in patients with autoimmune uveitis and experimental models, the study mapped a GPR183→cAMP-PKA suppression→son-of-sevenless→KRAS→mitochondrial oxidative stress pathway. It then identified fluvoxamine as a direct GPR183 antagonist via virtual screening, docking, and microscale thermophoresis.
• The result: In vivo and in vitro uveitis and colitis models, fluvoxamine attenuated GPR183–KRAS signaling, dampened pathogenic TH17 responses, and alleviated tissue inflammation, supporting repurposing for autoimmune inflammatory disorders.