A novel way of regression of pregnant corpus luteum during parturition in mice: The ferroptosis associated with NCOA4-mediated ferritinophagy

Abstract

Numerous studies have shown that inappropriate regression of corpus luteum would lead to adverse pregnancy outcomes during gestation. However, the detailed mechanisms and types of programmed cell death involved in the regression of pregnant corpus luteum are largely unknown. Here, we investigated whether ferroptosis and ferritinophagy were involved in luteal regression during parturition in mice and related mechanisms. The results showed that ferroptosis and ferritinophagy were both involved in luteal regression during mice peri-parturition in vivo. Erastin (ferroptosis agonist) treatment significantly accelerated luteal regression and induced premature labor in pregnant mice. PGF2α treatment induced the ferroptosis and ferritinophagy of luteal cells in vitro. Nevertheless, inhibition or promotion of ferroptosis significantly altered the states of PGF2α-induced luteal cell viability and ferroptosis. Furthermore, inhibition of autophagy (3-methyladenine co-treatment) alleviated PGF2α-induced ferritinophagy and ferroptosis of luteal cells, and knockdown of NCOA4 reduced the degradation of FTH1 and the level of ferroptosis of luteal cells induced by PGF2α. In summary, our current data demonstrated that the ferroptosis associated with NCOA4-mediated ferritinophagy was a novel way of luteal regression during peri-parturition in mice. Targeting ferroptosis in the corpus luteum may be a therapeutic strategy for preventing luteal insufficiency in the future.