F2RL2 (coagulation factor II thrombin receptor-like 2) is a G protein-coupled receptor that functions as a thrombin-activated receptor mediating phosphoinositide hydrolysis signaling 1. Beyond its canonical role in coagulation, F2RL2 has emerged as a multifunctional protein with significant disease relevance. In myocardial infarction, F2RL2 expression is upregulated and contributes to cardiac injury; F2RL2 downregulation prevents reduction in cardiac function and decreases myocyte apoptosis, while its expression is regulated by the NEAT1/miR-582-5p and miR-125b-5p/NFAT2 regulatory axes 2 1. In pancreatic cancer, elevated F2RL2 expression associates with improved survival and enhanced infiltration of CD8+ T cells and Th1 cells, suggesting an immune-protective role 3. Similarly, in esophageal squamous cell carcinoma and colon adenocarcinoma, F2RL2 functions as a favorable prognostic marker linked to immune activation 4 5. Novel evidence demonstrates F2RL2 protein expression in retinal cone photoreceptor outer segments and Müller glia, with increased expression in fibrotic areas during advanced age-related macular degeneration, implicating F2RL2 in ocular pathology 6. Additionally, F2RL2 mediates cell-cell crosstalk in gastrointestinal immune responses through GZMA signaling 7. These findings establish F2RL2 as a pleiotropic regulator linking coagulation pathways to immune function and tissue homeostasis across multiple organ systems.