Endocytosis of sialic acid Neu5Gc and elevated p53 contributes to preimplantation embryonic arrest during in vitro fertilization

Xin Yuan; Yilun Wu; Yi Zhang; Bin Yao; Linyu Zhang; Zhenqing Liu; Qianhong Ma; Fang Ma

doi:10.1016/j.jbc.2025.110254

Endocytosis of sialic acid Neu5Gc and elevated p53 contributes to preimplantation embryonic arrest during in vitro fertilization

J Biol Chem. 2025 Jun;301(6):110254. doi: 10.1016/j.jbc.2025.110254. Epub 2025 May 20.

Authors

Xin Yuan¹, Yilun Wu¹, Yi Zhang¹, Bin Yao¹, Linyu Zhang¹, Zhenqing Liu², Qianhong Ma³, Fang Ma⁴

Affiliations

¹ Center for Translational Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China; Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China.
² Department of Neurodegenerative Diseases, Beckman Research Institute of City of Hope, Duarte, California, USA; Epithelial Cell Biology Research Center, The Chinese University of Hong Kong, Hong Kong SAR, PR China. Electronic address: zhenqing.liu42@gmail.com.
³ Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China; Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China. Electronic address: maqh@scu.edu.cn.
⁴ Center for Translational Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China; Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China. Electronic address: mafangmed@126.com.

Abstract

The persistently low success rate of human in vitro fertilization (IVF) remains a major clinical challenge, despite significant technological advancements. While culture media composition is known to influence outcomes, the specific components affecting embryonic development are poorly understood. In this study, we identify N-glycolylneuraminic acid (Neu5Gc), a foreign sialic acid contaminant prevalent in animal-derived IVF media components, as a micro-environmental factor triggering developmental arrest. We demonstrate that Neu5Gc accumulates in arrested human embryos via endocytosis and upregulates p53, leading to caspase-3/PARP -dependent apoptotic pathways. This mechanism was validated in human embryonic stem cells (hESCs) and zebrafish embryos, with antibody-mediated Neu5Gc neutralization rescuing developmental defects. Our findings not only elucidate a novel pathway contributing to IVF inefficiency but also provide actionable insights for optimizing culture media formulations.

Keywords: In vitro fertilization; Neu5Gc; embryo development; hESCs; p53.

MeSH terms

Animals
Apoptosis
Blastocyst* / cytology
Blastocyst* / metabolism
Caspase 3 / metabolism
Embryonic Development
Endocytosis*
Fertilization in Vitro*
Human Embryonic Stem Cells / cytology
Human Embryonic Stem Cells / metabolism
Humans
Neuraminic Acids* / metabolism
Tumor Suppressor Protein p53* / genetics
Tumor Suppressor Protein p53* / metabolism
Zebrafish / embryology

Substances

Tumor Suppressor Protein p53
N-glycolylneuraminic acid
Neuraminic Acids
TP53 protein, human
Caspase 3