PRF1 encodes perforin 1, a pore-forming cytotoxic protein essential for immune-mediated cell death. PRF1 functions by inserting into target cell membranes in its calcium-bound form, oligomerizing to create large pores that facilitate the delivery of cytotoxic granzymes into target cells 12. This mechanism enables CD8+ T cells and natural killer cells to induce apoptosis in virus-infected, neoplastic, and allogeneic cells 34. PRF1 selectively delivers cationic cargo proteins while excluding anionic or neutral proteins, demonstrating substrate selectivity 4. PRF1 mutations cause familial hemophagocytic lymphohistiocytosis (fHLH), a life-threatening hyperinflammatory syndrome characterized by unremitting fever, cytopenias, and hepatosplenomegaly 5. In a large cohort of 1892 HLH patients, PRF1 mutations were the most frequent pathogenic variants identified 6. Beyond classical immunodeficiency, emerging evidence demonstrates that perforin production by CD8+ T cells drives intestinal epithelial CXCL9 production, which promotes neuroinflammation and depression in inflammatory bowel disease patients 7. Additionally, PRF1 expression marks cytotoxic CD4+ T cells (exTreg cells) in atherosclerosis and serves as a component of cytolytic T-lymphocyte transcriptomic signatures prognostic for survival in gastric cancer 89. These findings establish PRF1 as central to both protective immunity against pathogens and tumors and to pathological inflammation in multiple disease contexts.