SPAG4 (Sperm Associated Antigen 4) is a protein primarily involved in spermatogenesis and male fertility, with emerging roles in cancer biology. In its physiological function, SPAG4 is required for sperm head formation and anchoring of the manchette, specifically interacting with outer dense fiber protein ODF27 in elongating spermatids 1. The protein localizes to the inner nuclear membrane in spermatids and may play independent roles at the centriole-nucleus contact site 2. Beyond reproduction, SPAG4 has gained attention as an oncogene across multiple cancer types. In glioblastoma, SPAG4 overexpression correlates with poor prognosis and promotes cell proliferation and migration through MEK/ERK signaling pathway activation 3. Similarly, in colorectal cancer, SPAG4 enhances mitochondrial respiration and aerobic glycolysis by activating PI3K/Akt signaling 4. SPAG4 expression is regulated by hypoxia through HIF-1 in a VHL-dependent manner 5 and shows ERN1-dependent regulation under hypoxic conditions in glioblastoma cells 6. The protein has been identified as a potential therapeutic target and biomarker, particularly in glioblastoma where it may contribute to immune evasion by increasing CD47 expression 7.