DKKL1 (dickkopf like acrosomal protein 1) is a mammalian-specific secreted glycoprotein localized to the sperm acrosome with roles in male fertility and testicular homeostasis. 1 The protein accumulates in the acrosome during spermatogenesis and undergoes post-translational modifications, including N-glycosylation, during sperm development. 1 Mechanistically, DKKL1 functions as a negative regulator of adult testis homeostasis through two primary pathways. 2 First, it promotes postpubertal spermatocyte apoptosis via the Fas death ligand (FasL), as evidenced by elevated sperm counts and decreased apoptosis in DKKL1-deficient males. 2 Second, DKKL1 suppresses testosterone biosynthesis by inhibiting steroidogenic factor 1 transcriptional activity in Leydig cells, reducing expression of steroidogenic enzymes CYP11A and CYP17. 2 As a Dickkopf family member, DKKL1 may also antagonize Wnt/β-catenin signaling through Lrp5/6 inhibition. 3 Despite associations with male and female infertility disorders listed in disease databases, DKKL1 is not essential for development or fertility, as DKKL1-null mice remain viable and fertile. 4 However, DKKL1 downregulation correlates with asthenospermia (reduced sperm motility), suggesting functional importance in sperm quality. 5 Recent Mendelian randomization analysis identified DKKL1 as a potential therapeutic target for colorectal cancer, with genetically predicted elevated levels associated with increased CRC risk. 6