Progesterone-KISS1 axis impairs amniotic epithelial cell function and promotes premature rupture of membranes

Premature rupture of membranes (PROM) is a major cause of preterm birth and perinatal morbidity. Disruption of fetal membrane integrity is central to PROM pathogenesis; however, the molecular mechanisms underlying membrane weakening remain incompletely understood.

Proteomic analysis was performed on fetal membrane tissues from patients with early PPROM, late PPROM, full-term PROM, and full-term normal pregnancies. An LPS-induced infection-associated preterm birth mouse model was established to evaluate fetal membrane pathology, hormone levels, inflammatory responses, and Kisspeptin-1 (KISS1) expression. Human amniotic epithelial cells (hAECs) were used for in vitro studies to investigate the regulatory relationship between progesterone and KISS1 and their effects on cell viability, apoptosis, migration, and adhesion.

Proteomic profiling revealed significant upregulation of KISS1 in PROM, particularly in PPROM, accompanied by downregulation of adhesion-related proteins and enrichment of steroid metabolic pathways. In PROM mice, fetal membranes exhibited structural disruption, reduced progesterone levels, elevated inflammatory cytokines, and increased KISS1 expression. In hAECs, progesterone treatment suppressed KISS1 expression, whereas inhibition of progesterone signaling upregulated KISS1. Conversely, KISS1 overexpression reduced progesterone secretion, while KISS1 knockdown increased progesterone levels, indicating a reciprocal regulatory relationship. Progesterone inhibition impaired hAEC viability, enhanced apoptosis, reduced migration, and decreased expression of adhesion proteins FN1 and VTN. These effects were partially reversed by KISS1 knockdown.

The progesterone-KISS1 regulatory axis plays a critical role in maintaining amniotic epithelial cell function and fetal membrane integrity. Dysregulation of this axis promotes cellular dysfunction and contributes to PROM, highlighting KISS1 as a potential biomarker and therapeutic target.