KLRF1 (killer cell lectin-like receptor F1) is a type II transmembrane glycoprotein and activating receptor expressed on NK cells, subsets of T cells, and other hematopoietic cells 1. As an activating receptor, KLRF1 engages ligands including activation-induced C-type lectin (AICL) displayed on myeloid and tumor cells, stimulating NK cell cytotoxicity and cytokine production through SRC and SYK kinase activation 2. KLRF1 serves as a marker of CD56bright NK cells with enhanced activation and effector function 3. Clinically, KLRF1 has emerged as a diagnostic biomarker in multiple pathologies: it is identified as a hub gene in systemic lupus erythematosus and inflammatory bowel disease, likely reflecting dysregulated NK cell immunity 4, is differentially expressed in pulmonary fibrosis subtypes with higher expression in systemic sclerosis-associated ILD 5, and is downregulated in Kashin-Beck disease 6. In bladder cancer, high intratumoral KLRF1 expression on NK cells correlates with improved survival outcomes 3. Additionally, KLRF1+ NK-like innate lymphoid cells expand following checkpoint inhibitor therapy in hepatocellular carcinoma and associate with better progression-free survival 7. These findings underscore KLRF1's dual role as both a functional NK cell activation marker and a promising prognostic biomarker across diverse immune-mediated and malignant conditions.