SPINK2 (serine peptidase inhibitor Kazal type 2) is a serine protease inhibitor with dual roles in reproductive and hematopoietic contexts. Classically, SPINK2 functions as a strong inhibitor of acrosin and trypsin, preventing premature protease activation during spermiogenesis and supporting male fertility 1. However, emerging evidence reveals broader biological significance. SPINK2 is expressed in hematopoietic stem and progenitor cells (HSPCs) where it serves as a signature marker distinguishing HSCs from progenitors throughout human gestation 2. In bone marrow, SPINK2 likely participates in intercellular communication within the HSC niche through temporary inhibition of target proteases PRSS2 and PRSS57 3. In acute myeloid leukemia (AML), high SPINK2 expression emerges as an independent adverse prognostic marker associated with therapy resistance and relapse risk 4. SPINK2 expression is also linked to ferroptosis regulation and immune response suppression, identifying it as a potential therapeutic target 4. Additionally, genome-wide association studies identified SPINK2 variants as specific risk alleles for migraine without aura 5. Mutations in SPINK2 cause spermatogenic failure 29, confirming its essential reproductive function 6.