SPAG11B is a testis-epididymis-expressed antimicrobial protein structurally and functionally related to beta-defensins. It exhibits salt-tolerant antimicrobial activity against E. coli through an amphipathic, beta-sheet-rich structure resistant to pH and ionic strength variations 1. In the male reproductive tract, SPAG11B contributes to sperm maturation, protection, and innate host defense 23. Androgen-independent expression of SPAG11B contrasts with partial androgen regulation of related SPAG11A, suggesting distinct regulatory mechanisms for beta-defensin family members 2. SPAG11B interacts with tryptase alpha/beta 1, tetraspanin 7, and attractin, functioning in immunity and fertility pathways 3. Clinically, SPAG11B serves as a testis-specific biomarker with near-absolute specificity and sensitivity for discriminating nonobstructive azoospermia from normal seminal plasma, potentially eliminating need for testicular biopsy 4. Genetic deletions of SPAG11B associate with idiopathic azoospermia and oligoasthenozoospermia 5. Recent evidence identifies circulating SPAG11B as protective against cataract 6 and ankylosing spondylitis 7, suggesting pleiotropic functions beyond reproduction. Gut microbiota-derived metabolites show causal relationships with SPAG11B expression and male infertility 8.