Metabolite-gated vascular contractility switch: OXGR1 activation mechanism enables agonist therapy for rosacea erythema PMID: 41791372

ADC Targets in Oncology

2026-04-10

Metabolite-gated vascular contractility switch: OXGR1 activation mechanism enables agonist therapy for rosacea erythema

Cell. 2026 Apr 2;189(7):1990-2006.e30. doi: 10.1016/j.cell.2026.01.036.

Wenqin Xiao ¹ , Yan Zhu ¹ , Xinjie Tang ¹ , Kongkai Zhu ² , Weifeng Zhang ³ , Mengting Chen ¹ , Kui Cai ⁴ , San Xu ¹ , Zheng Wu ¹ , Mei Wang ¹ , Jiayi Liu ¹ , Linglong Long ¹ , Zixin Tan ¹ , Aike Wu ¹ , Songqi Zhou ¹ , Zhixiang Zhao ¹ , Yan Tang ¹ , Yingxue Huang ¹ , Ben Wang ¹ , Fangfen Liu ¹ , Qian Wang ⁵ , Fan Yang ³ , Dan Jian ¹ , Wei Shi ¹ , Hongfu Xie ⁶ , Xiang Chen ⁷ , Lulu Guo ⁸ , Zhili Deng ⁹ , Jinpeng Sun ¹⁰ , Ji Li ¹¹

Affiliations

1. Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Aging Biology, Xiangya Hospital, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Diseases (Xiangya Hospital), Central South University, Changsha, Hunan, China; FuRong Laboratory, Changsha, Hunan, China.
2. Advanced Medical Research Institute, Cheeloo College of Medicine, the Second Qilu Hospital, Shandong University, Jinan, Shandong, China.
3. Key Laboratory Experimental Teratology of the Ministry of Education and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
4. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China.
5. Hunan Binsis Biotechnology Co., Ltd, Changsha, Hunan, China.
6. Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; The First Hospital of Changsha, Changsha, China; The Affiliated Changsha Hospital of Xiangya School of Medicine, Central South University, Changsha, China.
7. Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Diseases (Xiangya Hospital), Central South University, Changsha, Hunan, China; FuRong Laboratory, Changsha, Hunan, China.
8. Advanced Medical Research Institute, Cheeloo College of Medicine, the Second Qilu Hospital, Shandong University, Jinan, Shandong, China. Electronic address: [email protected].
9. Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Aging Biology, Xiangya Hospital, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Diseases (Xiangya Hospital), Central South University, Changsha, Hunan, China; FuRong Laboratory, Changsha, Hunan, China. Electronic address: [email protected].
10. Advanced Medical Research Institute, Cheeloo College of Medicine, the Second Qilu Hospital, Shandong University, Jinan, Shandong, China; NHC Key Laboratory of Otorhinolaryngology, Qilu Hospital of Shandong University, Jinan, Shandong, China; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China. Electronic address: [email protected].
11. Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Aging Biology, Xiangya Hospital, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Diseases (Xiangya Hospital), Central South University, Changsha, Hunan, China; FuRong Laboratory, Changsha, Hunan, China. Electronic address: [email protected].

Abstract

Rosacea, an inflammatory skin disorder, poses a dilemma owing to limited effectiveness of treatments for pathological vasodilation-mediated erythema. Here, we identify oxoglutaric acid (α-KG) as a rosacea-associated metabolite elevated in patients and correlated with erythema severity. Exogenous α-KG administration ameliorates rosacea-like manifestations in murine models. Mechanistically, α-KG activates OXGR1, a vascular smooth muscle cell (VSMC)-enriched G protein-coupled receptor (GPCR) to induce Gq signaling and enhance MYL9 phosphorylation, promoting VSMC contraction and limiting vasodilation. Cryo-electron microscopy (cryo-EM) structures of OXGR1-Gq complexes bound to α-KG or itaconate reveal a specific bipartite-acid pocket recognizing its endogenous agonist and an activation mechanism distinct from classical GPCRs. Building on these structures, we developed A-1, a synthetic selective OXGR1 agonist that mitigates erythema and inflammation with efficacy comparable to first-line therapy while offering enhanced safety in rosacea-like models. These findings link a metabolite to vascular dysfunction and nominate OXGR1 agonism for precision treatment of erythema and vascular disorders.

Keywords

OXGR1; cryo-EM; oxoglutaric acid; rosacea; vasodilation.