Targeting EGFR–REM2–Ca2+ signaling and LDHA: amphiregulin remodels energy metabolism to enhance aged embryo development

Advances in assisted reproductive technology (ART) have expanded treatment options for many infertile families. However, outcomes in women of advanced maternal age remain suboptimal, primarily due to fewer retrievable oocytes and diminished embryonic developmental competence. In this study, we show that adding an appropriate concentration of amphiregulin (AREG) to the embryo culture medium significantly enhances the developmental competence of embryos from aged mice. Mechanistically, AREG binds to the epidermal growth factor receptor and induces receptor phosphorylation, thereby upregulating Ras like protein REM2. REM2 suppresses voltage gated calcium channel-mediated Ca²⁺ influx, reducing the elevated Ca²⁺ levels observed in aged embryos relative to young embryos and maintaining ATP supply. The improvement in ATP levels, in turn, restrains the excessive expression of LDHA in aged embryos, thereby decreasing pyruvate to lactate conversion and global protein lactylation, ultimately shifting embryonic physiology toward a more youthful state. These findings support supplementation with AREG during embryo culture as a rational strategy to improve ART outcomes in women of advanced maternal age.