REVIEW article
Front. Cell Dev. Biol.
Sec. Embryonic Development
This article is part of the Research TopicMetabolic Pathways in Early Embryogenesis: Mechanisms and ImplicationsView all articles
Linking the Warburg Effect to Endometrial Receptivity: Metabolic Parallels in Embryo Implantation
Provisionally accepted
- 1Beijing University of Chinese Medicine School of Traditional Chinese Medicine, Beijing, China
- 2Beijing University of Chinese Medicine, Beijing, China
- 3Beijing University of Chinese Medicine Dongfang Hospital, Beijing, China
- 4Beijing University of Chinese Medicine Affiliated Dongzhimen Hospital, Beijing, China
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Introduction: Endometrial receptivity (ER), critical for successful embryo implantation and a major limiting factor in infertility affecting ~1 in 6 couples globally, remains poorly understood, with few effective interventions targeting the embryo-endometrium interaction. Intriguingly, similarities exist between the implantation microenvironment and the Warburg effect, a metabolic hallmark of cancer characterized by aerobic glycolysis, lactate production, and low pH. Methods: We conducted a comprehensive review (PubMed search up to April 2025) using keywords related to the Warburg effect (aerobic glycolysis, lactate, mitophagy), infertility (IVF, embryo implantation, TCM), cancer, cytokines (IL-1, LIF, TGF-β), and hormones (estrogen, progesterone). Results: The review identified significant mechanistic parallels: 1) Blastocysts and trophoblasts establish a pro-receptive, high-lactate/low-pH microenvironment via Warburg-like glycolysis; 2) Shared immune modulation occurs (e.g., PI3K-AKT-FOXO1 pathway), balancing inflammatory attachment and immune tolerance; 3) Glycolysis regulates key ER-associated genes (e.g., MRAP2, BCL2L15) and cytokines (IL-1, LIF, TGF-β); 4) Invasive trophoblast behavior mirrors cancer cell invasion, potentially fueled by Warburg metabolism; 5) Hormones (estrogen, progesterone) critically orchestrate glycolytic enzyme expression (e.g., GLUT1, PFKFB3), substrate availability, and lactate-mediated immune suppression to establish this metabolic state. Discussion: While direct experimental evidence linking the Warburg effect to ER is currently limited, the compelling mechanistic overlap offers a novel paradigm for understanding implantation failure. Targeting this shared metabolic-immune-hormonal axis holds immense potential for developing innovative strategies (e.g., metabolic modulators, refined TCM approaches) to improve ER, enhance embryo implantation rates in infertility (including IVF) and recurrent miscarriage, ultimately advancing global reproductive health. Further research is needed to validate core mechanisms.
Keywords: Warburg effect1, endometrial receptivity2, embryo implantation3, Infertility4, Glycolysis5
Received: 11 Aug 2025; Accepted: 29 Oct 2025.
Copyright: © 2025 zhang, zhu, nie, yan, yuan and tian. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: qingwen zhu, bucm@qq.com
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