Ovarian-derived SERPINA1 contributes to zona pellucida integrity and serves as a serum indicator of follicular health in primary ovarian insufficiency

Primary ovarian insufficiency (POI) is often diagnosed too late for effective fertility intervention. Using data-independent acquisition (DIA) proteomics, we identified 405 differentially expressed serum proteins in young women with early POI. Among them, SERPINA1 was significantly downregulated and validated in an independent cohort (40 POI vs. 40 controls, p < 0.01). Immunohistochemistry revealed that SERPINA1 is enriched in the zona pellucida (ZP) of human and mouse antral/mature follicles—a previously unreported localization—absent in primordial follicles, suggesting stage-specific expression. In a cyclophosphamide/busulfan-induced POI mouse model, ovarian SERPINA1 was markedly reduced despite preserved ZP1 staining. These findings identify SERPINA1 as a follicle maturation–associated protein whose systemic decline correlates with early ovarian dysfunction. We propose that serum SERPINA1 may serve as a novel, tissue-informed candidate biomarker for non-invasive detection of incipient POI, potentially enabling earlier diagnosis and fertility preservation.