Inhibition of NHE1 induces trophoblast cell senescence via ADGRG6 mediated by CXCL8

Trophoblast cell senescence is a physiological process during early pregnancy, yet excessive senescence has an adverse influence on cellular behaviors and is closely related to unexplained recurrent spontaneous abortion (URSA). However, the specific regulatory mechanisms have not been well appreciated. In this study, we collected chorionic villi samples from 10 healthy women and 10 patients with RSA to examine the expression of NHE1. We also used trophoblast cell line HTR-8/SVneo to assess the role of NHE1 in cell senescence and invasion. We found that NHE1 expression was significantly reduced in RSA villi, coinciding with impaired invasion and enhanced cell senescence. Mechanistically, inhibition of NHE1 remarkably downregulated the level of CXCL8 and its downstream effector ADGRG6 that was also diminished in villous tissues from RSA patients. Notably, overexpression of ADGRG6 or supplementation with IL-8 partially ameliorated trophoblast functions. In summary, our findings revealed that NHE1 inhibition regulated trophoblast senescence and invasive behavior through downregulating CXCL8 and ADGRG6, providing novel mechanistic insights into the pathogenesis of URSA.