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<p>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 Ca<sup>2+</sup> influx, reducing the elevated Ca<sup>2+</sup> 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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年12月27日

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  • Dandan Yang,
  • Menghan Chai,
  • Kuanjian Zhang,
  • Qiqi Zhang,
  • Chao Zhang,
  • Huijuan Zou,
  • Weiwei Zou,
  • Lanxin Xie,
  • Min Xiong,
  • Tingting Ye,
  • Beili Chen,
  • Zhiguo Zhang

摘要

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.