SPINK2 encodes a serine protease inhibitor with dual roles in reproduction and hematopoiesis. In the testis and seminal vesicle, SPINK2 functions as a strong inhibitor of acrosin and trypsin, preventing premature activation of proacrosin during spermiogenesis and protecting against defects in male fertility 1. The gene is expressed in hematopoietic stem and progenitor cells (HSPCs), where it acts as a temporary protease inhibitor regulating intercellular communication within the hematopoietic niche through inhibition of PRSS2 and PRSS57 2. SPINK2 is part of the HSC transcriptome signature that distinguishes hematopoietic stem cells from progenitors throughout human gestation 3. Clinically, SPINK2 has emerged as a prognostic marker in acute myeloid leukemia (AML), where high protein expression associates with NPM1 mutations, intermediate cytogenetic risk, elevated therapy resistance, and adverse survival 4. SPINK2 regulates ferroptosis-related genes including SLC7A11 and STEAP3, affecting sensitivity to the ferroptosis inducer erastin, and modulates immune response by regulating ALCAM expression 4. A genome-wide association study identified a risk variant near SPINK2 specific to migraine without aura 5. In hepatocellular carcinoma, SPINK2 interacts with RARRES1 to suppress progression and enhance sensitivity to lenvatinib 6. Germline mutations in SPINK2 cause male infertility with azoospermia or oligozoospermia.