Lipid-sensing GPR183-KRAS signaling mediates TH17 autoimmunity and identifies fluvoxamine repurposing in uveitis
4 affiliations
- 1Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
- 2State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, China.
- 3Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200001, China.
- 4Key Laboratory of Sichuan Province Ophthalmopathy Prevention & Cure and Visual Function Protection With TCM, Chengdu, Sichuan 610000, China.
Abstract
Autoimmune uveitis (AU) is a leading cause of irreversible blindness driven by pathogenic T helper 17 (TH17) 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 TH17 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 TH17 cell responses, and alleviated tissue inflammation. These findings delineate a unique GPR183-KRAS-mitochondrial damage axis governing TH17-driven autoimmunity and support repurposing FLV as a translatable therapeutic approach for AU and other autoimmune inflammatory disorders.
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BibTeX
@article{zhang2026lipidsensing,
title = {{Lipid-sensing GPR183-KRAS signaling mediates TH17 autoimmunity and identifies fluvoxamine repurposing in uveitis}},
author = {Chun Zhang and Xiuxing Liu and Nanwei Xu and Hui Chen and Yuehan Gao and Chenyang Gu and Xinyue Shen and Junying Wu and Xuejing Lu and Pei Zhang and Yuxuan He and Zhuping Xu and Wenru Su},
journal = {Science Advances},
year = {2026},
month = oct,
doi = {10.1126/sciadv.aeh8465},
url = {https://www.science.org/doi/abs/10.1126/sciadv.aeh8465},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Lipid-sensing GPR183-KRAS signaling mediates TH17 autoimmunity and identifies fluvoxamine repurposing in uveitis
AU - Chun Zhang
AU - Xiuxing Liu
AU - Nanwei Xu
AU - Hui Chen
AU - Yuehan Gao
AU - Chenyang Gu
AU - Xinyue Shen
AU - Junying Wu
AU - Xuejing Lu
AU - Pei Zhang
AU - Yuxuan He
AU - Zhuping Xu
AU - Wenru Su
PY - 2026
DA - 2026/10/28
JO - Science Advances
DO - 10.1126/sciadv.aeh8465
UR - https://www.science.org/doi/abs/10.1126/sciadv.aeh8465
AB - Autoimmune uveitis (AU) is a leading cause of irreversible blindness driven by pathogenic T helper 17 (TH17) 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 TH17 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 TH17 cell responses, and alleviated tissue inflammation. These findings delineate a unique GPR183-KRAS-mitochondrial damage axis governing TH17-driven autoimmunity and support repurposing FLV as a translatable therapeutic approach for AU and other autoimmune inflammatory disorders.
SN - 2375-2548
ER -