Lipid-sensing GPR183-KRAS signaling mediates T _H 17 autoimmunity and identifies fluvoxamine repurposing in uveitis

Autoimmune uveitis (AU) is a leading cause of irreversible blindness driven by pathogenic T helper 17 (T _H 17) cell–mediated inflammation, yet current therapies are limited by efficacy and side effects, with immunometabolic mechanisms remaining poorly defined. By integrating single-cell RNA sequencing and multilayered metabolomic profiling in patients with AU and experimental AU models, we identified the lipid-sensing G protein–coupled receptor GPR183 as a key immunometabolic regulator in pathogenic CD4 ⁺ T cells. Upon activation, GPR183 modulates intracellular signaling via suppression of cyclic adenosine monophosphate–cAMP-dependent protein kinase activity and promotion of son-of-sevenless–dependent KRAS activation, which in turn elicits copper overload–induced mitochondrial oxidative stress, structural impairment, and metabolic rewiring toward glycolysis, thereby promoting T _H 17 cell pathogenicity. For clinical translation, virtual screening of Food and Drug Administration–approved drugs coupled with molecular docking and microscale thermophoresis validation identified fluvoxamine (FLV) as a direct GPR183 antagonist. In in vivo and in vitro uveitis and colitis models, FLV attenuated GPR183-KRAS signaling, dampened pathogenic T _H 17 cell responses, and alleviated tissue inflammation. These findings delineate a unique GPR183-KRAS–mitochondrial damage axis governing T _H 17-driven autoimmunity and support repurposing FLV as a translatable therapeutic approach for AU and other autoimmune inflammatory disorders.