Xiao et al. identify α-KG as a rosacea-associated metabolite that activates the OXGR1-Gq-MYL9 axis in the vascular smooth muscle cells to boost contractility and suppress pathological vasodilation underlying erythema. Cryo-EM reveals a bipartite-acid pocket of OXGR1 that enables structure-guided development of A-1, a selective agonist that alleviates erythema in rosacea-like models.

Histidine scanning represents a broadly applicable technique for the identification of critical interaction sites within TCRs and other mechanosensory receptors to enhance receptor signaling strength and augment therapeutic efficacy via the catch bond mechanism.