F2rl3, also known as F2R like thrombin or trypsin receptor 3 or PAR-4, encodes protease-activated receptor 4, a potent thrombin receptor expressed on platelets. Thrombin plays a role in platelet activation, and alterations in this biological pathway related to F2rl3 could be important for ischemic cardiovascular disease. Also, it is involved in other biological processes like the Rap1/MAPK signaling pathway in gastric cancer, and may have a role in processes related to osteoarthritis, pulmonary hypertension, and more [1,2,3,4].

In the context of smoking-related diseases, DNA hypomethylation at the F2RL3 locus has been associated with increased risk of myocardial infarction. Smoking-induced epigenetic DNA hypomethylation at F2RL3 appears to increase PAR4 expression, influencing platelet reactivity. In gastric cancer, knockdown of F2RL3 affects the angiogenesis and epithelial-mesenchymal transition (EMT) of gastric cells through the Rap1/MAPK pathway. Blood-based F2RL3 methylation is associated with the risk of coronary heart disease, especially in the elderly and those with myocardial infarction. Additionally, F2RL3 methylation is strongly associated with lung cancer incidence and mortality, and is a biomarker for smoking exposure and a predictor of all-cause, cardiovascular, and cancer mortality [1-3,5-7,9].

In conclusion, F2rl3 is crucial in multiple biological processes and disease conditions. Its role in platelet activation and related pathways impacts cardiovascular diseases, and its involvement in signaling pathways like Rap1/MAPK in cancer shows its significance in tumor development. The associations of F2RL3 methylation with various diseases, especially those related to smoking, highlight its potential as a biomarker and a key factor in understanding disease mechanisms.