F2RL1 (Protease-Activated Receptor 2, PAR2) is a G protein-coupled receptor that recognizes trypsin and serine proteases, serving as a critical sensor of proteolytic activity in multiple physiological contexts 1. The receptor activates diverse intracellular signaling pathways including phospholipase C, calcium mobilization, MAPK, NF-κB, and Rho, enabling broad cellular responses 1. F2RL1 plays dual roles in barrier function and inflammation. It maintains intestinal epithelial integrity and lysosomal autophagy through FOXA2-mediated ATP6V0E1 transcription, protecting against colitis-associated colorectal cancer 2. Conversely, F2RL1 activation promotes inflammatory responses by regulating leukocyte recruitment, dendritic cell maturation, and cytokine production 1. Bacterial proteases, including Bacteroides fragilis serine protease 1, exploit F2RL1 to disrupt intestinal barriers and trigger colonic inflammation 3. In disease contexts, elevated F2RL1 expression associates with poor prognosis in cervical cancer, correlating with reduced immune infiltration and immune evasion 4. PAR2 activation also induces cellular senescence in kidney disease, promoting renal fibrosis 5. Conversely, in auditory hair cell regeneration, proteolytic F2RL1 activation initiates a cascade through HBEGF-EGFR-ERK signaling essential for supporting cell proliferation 6. These findings establish F2RL1 as a context-dependent regulator of inflammation, barrier function, and tissue regeneration.