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].
PMID: 41791372 DOI: 10.1016/j.cell.2026.01.036
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.
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