LY6K (lymphocyte antigen 6 family member K) is a GPI-linked protein normally expressed in testes 1 that plays critical roles in both reproductive and cancer biology. In normal physiology, LY6K is required for sperm migration into the oviduct and male fertility through binding of sperm to zona pellucida. In cancer, LY6K functions as a putative oncogene with significantly elevated expression across multiple solid tumors including breast, ovarian, gastrointestinal, head and neck, brain, bladder, and lung cancers 1. Mechanistically, LY6K promotes cancer cell proliferation and survival through multiple signaling pathways. It regulates ERK-AKT and TGF-β pathways in cancer cells 1 and controls both clathrin- and caveolin-1-mediated endocytosis of TGF-β and EGF receptors 2. Additionally, LY6K signals through aurora B kinase to regulate cell cycle progression and mitosis 1. LY6K expression is transcriptionally regulated by AP-1 transcription factors, with SNP242 and CpG methylation reducing expression 3. Clinically, elevated LY6K expression strongly correlates with poor prognosis and survival outcomes across multiple cancer types 14. LY6K silencing inhibits cancer cell proliferation, migration, invasion, and tumor growth in vivo 5, making it a promising therapeutic target, particularly for treatment-resistant cancers 1.