GPX3 improves endometrial receptivity by inhibiting ferroptosis via the Nrf2/GPX4 signaling pathway in sows.

Obesity represents a major contributor to reproductive dysfunction during early mammalian pregnancy, yet the underlying mechanisms by which it impairs endometrial receptivity remain largely unknown. Through integrative metabolomic and transcriptomic profiling of uterine tissues from obese and control sows on gestational day 13, glutathione peroxidase 3 (GPX3) was identified as a key molecular determinant of endometrial receptivity. GPX3 expression was markedly reduced in the uterine tissue of obese sows and was closely associated with impaired receptivity. Functionally, GPX3 knockdown induced mitochondrial dysfunction, perturbed lipid peroxidation homeostasis, and triggered ferroptosis, ultimately reducing endometrial receptivity in palmitic acid (PA)-induced porcine endometrial epithelial cells (PEECs). In contrast, GPX3 overexpression restored mitochondrial function and suppressed ferroptotic signaling. Mechanistically, GPX3 deficiency activated ferroptosis via inhibition of the nuclear factor erythroid 2-related factor 2 (Nrf2)/GPX4 axis. Consistent with these findings, high-fat diet (HFD)-induced obese female mice exhibited reduced endometrial receptivity, down-regulation of the GPX3/Nrf2/GPX4 cascade, and mitochondrial ultrastructural damage. Overall, these findings establish GPX3 as a pivotal regulator of endometrial receptivity through modulation of Nrf2/GPX4-dependent ferroptotic signaling, providing novel insights into obesity-associated reproductive disorders.