SPINT4 (serine peptidase inhibitor, Kunitz type 4) is a Kunitz-domain-containing protein predominantly expressed in the epididymis 1, localizing to a conserved gene cluster on human chromosome 20 with other reproductive tract-specific protease inhibitors 2. The protein is secreted (8.7 kDa) and structurally related to WFDC-type protease inhibitors despite lacking sequence similarity to classical serine protease inhibitors 1. SPINT4 exhibits restricted epididymis-specific expression, suggesting a specialized reproductive function 3. Functionally, SPINT4 is critical for male fertility; CRISPR/Cas9 knockout studies demonstrate that deletion of Spint4 (together with Spint5 and Ces5a) impairs male mouse fertility, whereas Spint4 single knockout results were not separately detailed 3. Evolutionary analysis reveals SPINT4 is a target of recent positive selection (incomplete selective sweep) in African populations, with a haplotype configuration [Ser73+98A] potentially affecting protein function and gene regulation, suggesting adaptive importance in human reproductive physiology 4. While the precise molecular targets and protease inhibitory spectrum remain incompletely characterized 1, SPINT4's essential role in male fertility and evolutionary conservation indicate it represents a potential target for male contraceptive development 32.