FPR2 is a G protein-coupled receptor functioning as a pattern recognition receptor for formylated peptides derived from pathogens and host mitochondria, particularly recognizing longer peptides and Staphylococcus aureus phenol-soluble modulins 1. Ligand binding triggers Gi/GNAI1-mediated signaling that inhibits adenylate cyclase and decreases intracellular cAMP 2. Beyond formylpeptides, FPR2 recognizes diverse endogenous ligands including ANXA1, lipoxins, ceramides (C14-C20), and the chemokine-like protein FAM19A5, enabling multiple physiological roles 324. FPR2 mediates anti-inflammatory responses: ANXA1-FPR2 signaling on fibroblasts maintains tissue homeostasis, while lipoxin signaling promotes resolution of inflammation 34. Ceramide binding inhibits adipocyte thermogenesis through cAMP pathways 2. Dysregulated FPR2 signaling associates with multiple diseases: esophageal cancer development via loss of epithelial ANXA1, hypertension through FAM3D-mediated eNOS uncoupling, acute myocardial infarction, and neuromyelitis optica spectrum disorder where FPR2 antagonism reduces neuroinflammation and microglia activation 3567. FPR2 also regulates LC3-associated efferocytosis for intestinal inflammation control and influences influenza pathogenesis 89. Differential signaling occurs via oligomerization state and biased activation mechanisms.