OVCH2 (ovochymase 2) is an epididymis-specific serine-type endopeptidase required for male fertility 1. Located in the proximal caput epididymidis, OVCH2 functions as a secreted protease essential for sperm maturation and fertilizing ability 2. Mechanistically, OVCH2 operates downstream of a lumicrine signaling cascade: testicular NELL2 protein binds to the ROS1 receptor tyrosine kinase in the epididymal initial segment, triggering OVCH2 expression, which then processes the sperm surface protein ADAM3—a critical substrate for zona pellucida binding 1. Male mice lacking functional OVCH2 are infertile due to impaired sperm-egg interaction 1. Clinically, OVCH2 dysfunction occurs when ROS1 signaling is disrupted; lorlatinib-treated mice showed decreased OVCH2 expression, abnormal sperm maturation, and reduced fertility that reversed upon drug discontinuation 3. The catalytic protease domain, rather than the C-terminal CUB domains, is critical for OVCH2 fertility function 2. These findings suggest OVCH2 represents a potential non-hormonal male contraceptive target and indicate the protease domain should be prioritized in genetic screening of infertile men 2.