KLRC3 (killer cell lectin-like receptor C3) is an NK cell surface receptor that recognizes MHC class I HLA-E molecules and participates in natural killer cell-mediated immunity and cellular defense responses. KLRC3 functions as an activating receptor that positively regulates NK cell cytotoxicity through stimulatory C-type lectin receptor signaling 1. Mechanistically, KLRC3 expression is regulated at multiple levels. DNA methylation status influences KLRC3 expression in autoimmune thyroiditis, with KLRC3 showing hypermethylation alongside elevated mRNA expression 2. MicroRNA-141 directly targets KLRC3, suppressing its expression and promoting cervical cancer cell proliferation and migration 3. Additionally, the metabolite fumarate produced by adenylosuccinate lyase regulates KLRC3 expression in endometrial cancer cells 4. Clinically, KLRC3 dysregulation associates with multiple pathologies. KLRC3 overexpression drives glioblastoma aggressiveness by enhancing cancer stem cell self-renewal, invasion, and radioresistance; KLRC3 silencing reduced these tumorigenic properties 1. KLRC3 serves as a candidate diagnostic gene for repeated implantation failure with antiphospholipid syndrome 5 and emerged as a prognostic immune-associated gene in lung adenocarcinoma 6. KLRC3 was identified as an immune hub gene in Vogt-Koyanagi-Harada autoimmune disease 7 and shows differential expression in Kashin-Beck disease 8. These findings position KLRC3 as a multifunctional immune receptor with significant potential as a therapeutic target across cancer and autoimmune conditions.