Metabolite-gated vascular contractility switch: OXGR1 activation mechanism enables agonist therapy for rosacea erythema - PubMed
3 days ago
- #rosacea
- #OXGR1
- #vascular disorders
- Oxoglutaric acid (α-KG) is identified as a rosacea-associated metabolite, elevated in patients and correlated with erythema severity.
- α-KG activates OXGR1 in vascular smooth muscle cells (VSMCs), inducing Gq signaling and enhancing MYL9 phosphorylation, leading to VSMC contraction and reduced vasodilation.
- Cryo-EM structures reveal OXGR1-Gq complexes bound to α-KG or itaconate, showing a unique bipartite-acid pocket and activation mechanism distinct from classical GPCRs.
- A synthetic selective OXGR1 agonist, A-1, was developed, showing efficacy in mitigating erythema and inflammation in rosacea-like models with enhanced safety.
- The findings suggest OXGR1 agonism as a potential precision treatment for erythema and vascular disorders.