Editorial: Metabolic pathways in early embryogenesis: mechanisms and implications

Marcella Pecora Milazzotto, Marcos Roberto Chiaratti, Jo Leroy, Camila Bruna de Lima

contributions assembled in this Research Topic, "Metabolic Pathways in Early Embryogenesis: Mechanisms and Implications," collectively underscore that metabolism is not a passive background process but a primary driver and regulator of early development, with implications for implantation, fetal health, and assisted reproduction.A central theme emerging from this collection is that metabolic pathways are linked to the formation and functional specialization of the earliest embryonic lineages. A second major theme is the extension of metabolic regulation beyond the embryo proper to encompass endometrial receptivity and the peri-implantation interface.The work by Zhang et al. provides a comprehensive review highlighting the emerging parallels between the Warburg effect and endometrial receptivity, proposing that embryo implantation relies on metabolic adaptations similar to those observed in rapidly proliferating cancer cells. The authors discuss evidence that blastocysts and trophoblasts establish a lactate-rich, acidic microenvironment through aerobic glycolysis, which promotes endometrial receptivity by modulating immune tolerance, cytokine signaling, epigenetic regulation, and trophoblast invasion. The review further integrates current knowledge on the roles of glycolytic metabolism, mitochondrial dynamics, histone lactylation, and hormone-dependent regulation in coordinating embryo-endometrium communication. Although direct experimental evidence remains limited, this work presents a compelling conceptual framework linking metabolic reprogramming to implantation success and identifies the Warburg-like metabolic state as a promising target for improving endometrial receptivity and reproductive outcomes.If metabolism shapes not only the embryo and uterus but also our capacity to assess and select viable embryos, then there is a pressing need for robust, non-invasive metabolic analysis. This need is addressed by Cao et al., who present an original study combining Raman spectroscopy of day-3 spent culture medium with machine learning to predict the capacity of cleavage-stage human embryos to form good-quality blastocysts.Using Raman metabolic fingerprints from Day 3 culture media samples, the authors trained and compared twelve machine learning models to classify embryos according to their extended culture outcomes: morphologically good blastocysts, morphologically non-good blastocysts, or clinically non-useful embryos. A multilayer perceptron (MLP) achieved the best individual performance, while an ensemble stacking strategy further improved prediction, reaching an overall accuracy of 94%, with 93% sensitivity and 97% specificity. By integrating complex metabolic signatures rather than relying solely on embryo morphology, this approach provides an objective assessment of embryo quality and may allow reliable selection of high-potential embryos for transfer at the cleavage stage, potentially reducing the need for extended blastocyst culture and its associated risks. Although promising, the authors emphasize that larger, multicenter validation studies and randomized clinical trials are required before routine clinical implementation. This Research Topic illustrates how diverse approaches can be brought together to point to metabolism as a common principle in early embryogenesis. These articles collectively pave the way toward more physiologically informed embryo culture systems, better predictors of developmental competency, and improved reproductive outcomes.We hope that this collection will stimulate further interdisciplinary research at the interface of developmental biology, metabolism, reproductive medicine, and systems biology, and that it will help to shift the field from viewing metabolism as a background "support service" to recognizing it as a central actor of early life.