Cell · 2026

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

Xiao, W. and Zhu, Y. and Tang, X. and Zhu, K. and Zhang, W. and Chen, M. and Cai, K. and Xu, S. and Wu, Z. and Wang, M. and Liu, J. and Long, L. and Tan, Z. and Wu, A. and Zhou, S. and Zhao, Z. and Tang, Y. and Huang, Y. and Wang, B. and Liu, F. and Wang, Q. and Yang, F. and Jian, D. and Shi, W. and Xie, H. and Chen, X. and Guo, L. and Deng, Z. and Sun, J. and Li, J.

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.

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Cell 2026

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

Xiao, W. and Zhu, Y. and Tang, X. and Zhu, K. and Zhang, W. and Chen, M. and Cai, K. and Xu, S. and Wu, Z. and Wang, M. and Liu, J. and Long, L. and Tan, Z. and Wu, A. and Zhou, S. and Zhao, Z. and Tang, Y. and Huang, Y. and Wang, B. and Liu, F. and Wang, Q. and Yang, F. and Jian, D. and Shi, W. and Xie, H. and Chen, X. and Guo, L. and Deng, Z. and Sun, J. and Li, J.

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.

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Central South University Xiangya Hospital Li Lab Skin Aging and Hair Regeneration Research Center