PTGIR (prostaglandin I2 receptor) is a G protein-coupled receptor that mediates prostacyclin (PGI2) signaling through Gs protein activation of adenylate cyclase. 1 The receptor is expressed on multiple cell types including fibroblasts, myofibroblasts, CD8+ T cells, and intestinal fibroblasts, where it transduces anti-inflammatory and cytoprotective signals. 123 Mechanistically, PTGIR activation suppresses fibroblast activation and collagen production, inhibits T cell exhaustion through NRF2-dependent pathways, and opposes pro-fibrotic YAP/TAZ signaling in intestinal fibroblasts. 123 PTGIR also promotes CD8+ T cell effector function and limits exhaustion in chr19 infection and cancer contexts. 2 Dysregulation of PTGIR signaling is implicated in multiple disease pathologies. In chr19 kidney disease and Crohn's disease, decreased PGI2-PTGIR signaling contributes to fibrosis progression. 13 In endometriosis, PGI2-PTGIR signaling promotes immune tolerance by inhibiting NK cell function. 4 Mendelian randomization studies identify PTGIR as a protective factor against atrial fibrillation and prostatitis. 56 Genetic variants, particularly arginine-targeted mutations, may compromise cardioprotective effects. 7 PTGIR represents a tractable therapeutic target for fibrotic and inflammatory diseases.