F2RL3 encodes protease-activated receptor 4 (PAR4), a G protein-coupled receptor that responds to activated thrombin or trypsin and stimulates phosphoinositide hydrolysis 1. The receptor plays a crucial role in platelet activation and blood coagulation, with DNA hypomethylation at F2RL3 associated with increased platelet reactivity in response to PAR4 stimulation 1. F2RL3 expression is regulated epigenetically, with smoking-induced DNA hypomethylation leading to increased F2RL3 mRNA expression and contributing to cardiovascular disease risk through enhanced platelet activation 1. The gene shows tissue-specific expression patterns, being identified as a metabolic gene signature in pancreatic islet-specific endothelial cells 2. F2RL3 methylation status serves as a biomarker for various diseases: hypomethylation correlates with poor prognosis in coronary heart disease patients with hypertension 3, while reduced expression is associated with osteoarthritis 4. In pulmonary hypertension, F2RL3 is transcriptionally regulated by STING through NF-κB signaling, activating interferon pathways and repressing BMPR2 signaling 5. Additionally, F2RL3 methylation patterns show gender-specific differences and may serve as an early detection biomarker for male lung adenocarcinoma 6.