The adaptive response of the endometrium to the embryonic lactate signal.A, representative fluorescent images of ROS production (green) in human endometrial cancer cells (Ishikawa line) exposed to different concentrations of sodium L-lactate. Right panel, normalized fluorescent intensity of ROS. ∗ represents p < 0.05, ∗∗ represents p < 0.01 relative to control group. B, representative fluorescent images of TUNEL (green) and DAPI (blue) staining in Ishikawa cells exposed to different concentrations of sodium L-lactate. Right panel, quantification of TUNEL-positive Ishikawa cells following different treatments. ∗∗ represents p < 0.01 relative to the control group. C, the GSH/GSSG ratio in different sodium L-lactate concentrations treated Ishikawa cells was measured. ∗ represents p < 0.05. D, proliferation assay of Ishikawa cells exposed to 10 mM sodium L-lactate for 12 h and 24 h. ∗∗ represents p < 0.01, ∗ represents p < 0.05. E, the attachment of mouse blastocysts to Ishikawa cells was assayed after 24 and 48 h of coculture in serum-free medium supplemented with different concentrations of sodium L-lactate. Representative images are shown and the red arrows represent the firmly attached embryos, and the black arrows represent the degraded embryos. ∗∗ represents p < 0.01. F and G, uterine morphology (F) and the number of implantation sites (G) on day 5 after uterine horns at day 4 were injected with different treatments. ∗∗ represents p < 0.01. Red arrows represent the implantation sites. Scale bar = 200 μm (A, B, and E). Scale bar = 1 cm (F). H, schematic diagram of the endometrial response to embryonic lactate signals during implantation. Glycolytic metabolism is upregulated in the conceptus, thus the conceptus-derived lactate would serve as an embryonic signal to promote histone lactylation in the endometrium, which in turn participates in the regulation of redox homeostasis, apoptosis, cell proliferation, cell adhesion, and immune tolerance. Blue arrows represent lactate stimulation, red arrows represent ROS stimulation, and the green arrow represents ROS scavenging by GSH/GSSG homeostasis. ROS, reactive oxygen species.