This study identified family with sequence similarity 205, member A (FAM205A) as a clinically significant acrosomal protein critically implicated in male idiopathic infertility. Integrated proteomic analysis of sperm from in vitro fertilization (IVF) patients categorized by fertilization outcome (n = 12 per group; clinical validation, n = 267) revealed a strong correlation between FAM205A expression and fertilization success (76.3% in high-expression groups vs 15.4% in low-expression groups, P < 0.05), independent of standard semen parameters. Functional analyses utilizing pooled human sperm samples (n = 20 per group) revealed that low FAM205A expression led to a significantly decreased calcium-induced acrosome reaction response (28.9% vs 49.2% in high FAM205A expression, P < 0.01), a phenotype corroborated by anti-FAM205A antibody blockade (38.1% inhibition, P < 0.01). The clustered regularly interspaced short palindromic repeat (CRISPR)-associated protein 9 (Cas9) genome editing system (CRISPR-Cas9)-generated knockout mice lacking Fam205a1, which is the murine ortholog of human FAM205A, exhibited complete infertility, characterized by oligospermia, asthenozoospermia, teratozoospermia, disrupted acrosome formation, and significantly reduced sperm motility. Mechanistic studies in Fam205a1 knockout mice revealed that FAM205A deficiency induces spermatid apoptosis and impairs acrosomal exocytosis, a crucial process for sperm–egg fusion. The results demonstrate that FAM205A regulates fertility through two mechanisms: preserving structural integrity during spermiogenesis and facilitating the acrosomal reaction (AR). This study identified FAM205A as a reliable diagnostic biomarker for idiopathic male infertility and a potential treatment target in reproductive medicine.

Keywords: acrosome reaction; biomarker; FAM205A; fertilization failure; male infertility; sperm motility