Mechanistic Insights Into Recurrent Implantation Failure: The Lactate–H3K18la–SLC7A11 Axis Explored via Endometrial Organoid and Blastoid–Endometrial Cell Implantation Models

Abstract

Recurrent implantation failure (RIF) remains a major challenge in assisted reproductive technologies, with the underlying molecular mechanisms still largely unknown. Here, we conducted proteomic profiling and analysed publicly available single-cell RNA sequencing data, revealing a marked decrease in lactate dehydrogenase A (LDHA) expression in RIF cases. While traditionally considered a metabolic byproduct, it is now recognised to play a role in signalling and epigenetic regulation. Utilising human endometrial organoids, we demonstrated that lactate enhances human endometrial receptivity by promoting epithelial–mesenchymal transition (EMT) and upregulating histone H3 lysine 18 lactylation (H3K18la). Further multi-omics analyses identified solute carrier family 7 member 11 (SLC7A11) as an H3K18la-regulated target. Functional assays confirmed that lactate-induced H3K18la upregulates SLC7A11, thereby driving EMT and cellular migration. Notably, using a blastoid–endometrial cell implantation model, we demonstrated that SLC7A11 promotes both blastoid adhesion and expansion, highlighting its critical role in embryo–endometrial interactions. Collectively, leveraging multiple organoid systems, including endometrial organoids and blastoid–endometrial cell implantation models, our findings reveal a novel lactate–H3K18la–SLC7A11 axis that orchestrates endometrial epithelial plasticity and receptivity. In addition, this study established a robust methodological framework for investigating implantation mechanisms.

Keywords

blastoid–endometrial cell implantation model / endometrial organoid / endometrial receptivity / H3K18la / lactate / recurrent implantation failure

References

[1] L. Craciunas, I. Gallos, J. Chu, et al., “Conventional and Modern Markers of Endometrial Receptivity: A Systematic Review and Meta-Analysis,” Human Reproduction Update 25, no. 2 (2019): 202–223.

[2] Z. Z. Lai, Y. Wang, W. J. Zhou, et al., “Single-Cell Transcriptome Profiling of the Human Endometrium of Patients With Recurrent Implantation Failure,” Theranostics 12, no. 15 (2022): 6527–6547.

[3] H. Yang, J. Zhang, F. Yan, et al., “Ciliary IFT-B Transportation Plays an Important Role in Human Endometrial Receptivity Establishment and Is Disrupted in Recurrent Implantation Failure Patients,” Cell Proliferation 58, no. 7 (2025): e13819.

[4] S. RoyChoudhury, A. Singh, N. J. Gupta, et al., “Repeated Implantation Failure Versus Repeated Implantation Success: Discrimination at a Metabolomic Level,” Human Reproduction 31, no. 6 (2016): 1265–1274.

[5] C. Wang, Y. Lu, M. Ou, et al., “Risk Factors for Recurrent Implantation Failure as Defined by the European Society for Human Reproduction and Embryology,” Human Reproduction 40, no. 6 (2025): 1138–1147.

[6] P. Zhou, D. Mo, H. Huang, et al., “Integrated Transcriptomic Analysis Reveals Dysregulated Immune Infiltration and Pro-Inflammatory Cytokines in the Secretory Endometrium of Recurrent Implantation Failure Patients,” Lifestyle Medicine 3, no. 5 (2024): lnae036.

[7] J. M. Franasiak, D. Alecsandru, E. J. Forman, et al., “A Review of the Pathophysiology of Recurrent Implantation Failure,” Fertility and Sterility 116, no. 6 (2021): 1436–1448.

[8] J. Evans, L. A. Salamonsen, A. Winship, et al., “Fertile Ground: Human Endometrial Programming and Lessons in Health and Disease,” Nature Reviews. Endocrinology 12, no. 11 (2016): 654–667.

[9] W. Wang, F. Vilella, P. Alama, et al., “Single-Cell Transcriptomic Atlas of the Human Endometrium During the Menstrual Cycle,” Nature Medicine 26, no. 10 (2020): 1644–1653.

[10] S. Whitby, W. Zhou, and E. Dimitriadis, “Alterations in Epithelial Cell Polarity During Endometrial Receptivity: A Systematic Review,” Frontiers in Endocrinology 11 (2020): 596324.

[11] W. Zhou, M. Van Sinderen, K. Rainczuk, et al., “Dysregulated miR-124-3p in Endometrial Epithelial Cells Reduces Endometrial Receptivity by Altering Polarity and Adhesion,” Proceedings of the National Academy of Sciences of the United States of America 121, no. 41 (2024): e2401071121.

[12] J. Ran, H. H. Yang, H. P. Huang, et al., “ZEB1 Modulates Endometrial Receptivity Through Epithelial–Mesenchymal Transition in Endometrial Epithelial Cells In Vitro,” Biochemical and Biophysical Research Communications 525, no. 3 (2020): 699–705.

[13] K. Crha, P. Ventruba, J. Zakova, et al., “The Role of Mesenchymal–Epithelial Transition in Endometrial Function and Receptivity,” Ceská Gynekologie 84, no. 5 (2019): 371–375.

[14] H. Uchida, T. Maruyama, S. Nishikawa-Uchida, et al., “Studies Using an In Vitro Model Show Evidence of Involvement of Epithelial–Mesenchymal Transition of Human Endometrial Epithelial Cells in Human Embryo Implantation,” Journal of Biological Chemistry 287, no. 7 (2012): 4441–4450.

[15] B. Gellersen and J. J. Brosens, “Cyclic Decidualization of the Human Endometrium in Reproductive Health and Failure,” Endocrine Reviews 35, no. 6 (2014): 851–905.

[16] H. Zhang, J. Qi, Y. Wang, et al., “Progesterone Regulates Glucose Metabolism Through Glucose Transporter 1 to Promote Endometrial Receptivity,” Frontiers in Physiology 11 (2020): 543148.

[17] R. J. Zuo, X. W. Gu, Q. R. Qi, et al., “Warburg-Like Glycolysis and Lactate Shuttle in Mouse Decidua During Early Pregnancy,” Journal of Biological Chemistry 290, no. 35 (2015): 21280–21291.

[18] J. D. Rabinowitz and S. Enerback, “Lactate: The Ugly Duckling of Energy Metabolism,” Nature Metabolism 2, no. 7 (2020): 566–571.

[19] S. Dichtl, L. Lindenthal, L. Zeitler, et al., “Lactate and IL6 Define Separable Paths of Inflammatory Metabolic Adaptation,” Science Advances 7, no. 26 (2021): eabg3505.

[20] R. A. Irizarry-Caro, M. M. McDaniel, G. R. Overcast, V. G. Jain, T. D. Troutman, and C. Pasare, “TLR Signaling Adapter BCAP Regulates Inflammatory to Reparatory Macrophage Transition by Promoting Histone Lactylation,” Proceedings of the National Academy of Sciences of the United States of America 117, no. 48 (2020): 30628–30638.

[21] P. E. Porporato, V. L. Payen, C. J. De Saedeleer, et al., “Lactate Stimulates Angiogenesis and Accelerates the Healing of Superficial and Ischemic Wounds in Mice,” Angiogenesis 15, no. 4 (2012): 581–592.

[22] J. Yang, L. Luo, C. Zhao, et al., “A Positive Feedback Loop Between Inactive VHL-Triggered Histone Lactylation and PDGFRbeta Signaling Drives Clear Cell Renal Cell Carcinoma Progression,” International Journal of Biological Sciences 18, no. 8 (2022): 3470–3483.

[23] Y. Sun, Q. He, J. Li, et al., “A GSTP1-Mediated Lactic Acid Signaling Promotes Tumorigenesis Through the PPP Oxidative Branch,” Cell Death & Disease 14, no. 7 (2023): 463.

[24] X. Zhang, J. Chen, R. Lin, et al., “Lactate Drives Epithelial–Mesenchymal Transition in Diabetic Kidney Disease via the H3K14la/KLF5 Pathway,” Redox Biology 75 (2024): 103246.

[25] J. Pan, Y. Zhang, R. Yao, et al., “IGF1R Enhances Calcium Oxalate Monohydrate-Induced Epithelial–Mesenchymal Transition by Reprogramming Metabolism via the JAK2/STAT3 Signaling,” International Journal of Biological Sciences 21, no. 1 (2025): 415–432.

[26] J. L. Zhao, Y. C. Ye, C. C. Gao, et al., “Notch-Mediated Lactate Metabolism Regulates MDSC Development Through the Hes1/MCT2/c-Jun Axis,” Cell Reports 38, no. 10 (2022): 110451.

[27] D. C. Lee, H. A. Sohn, Z. Y. Park, et al., “A Lactate-Induced Response to Hypoxia,” Cell 161, no. 3 (2015): 595–609.

[28] T. Feng, X. Zhao, P. Gu, et al., “Adipocyte-Derived Lactate Is a Signalling Metabolite That Potentiates Adipose Macrophage Inflammation via Targeting PHD2,” Nature Communications 13, no. 1 (2022): 5208.

[29] D. Zhang, Z. Tang, H. Huang, et al., “Metabolic Regulation of Gene Expression by Histone Lactylation,” Nature 574, no. 7779 (2019): 575–580.

[30] Y. Hou, D. Liu, Z. Guo, et al., “Lactate and Lactylation in AKI-to-CKD: Epigenetic Regulation and Therapeutic Opportunities,” Cell Proliferation 58, no. 9 (2025): e70034.

[31] Q. Yang, J. Liu, Y. Wang, et al., “A Proteomic Atlas of Ligand–Receptor Interactions at the Ovine Maternal–Fetal Interface Reveals the Role of Histone Lactylation in Uterine Remodeling,” Journal of Biological Chemistry 298, no. 1 (2022): 101456.

[32] W. Zhao, Y. Wang, J. Liu, et al., “Progesterone Activates the Histone Lactylation–Hif1alpha–Glycolysis Feedback Loop to Promote Decidualization,” Endocrinology 165, no. 1 (2023): bqad169.

[33] Q. Tian and L. Q. Zhou, “Lactate Activates Germline and Cleavage Embryo Genes in Mouse Embryonic Stem Cells,” Cells 11, no. 3 (2022): 548.

[34] S. An, S. Hou, F. Xu, et al., “WDR36 Regulates Trophectoderm Differentiation During Human Preimplantation Embryonic Development Through Glycolytic Metabolism,” Advancement of Science 12, no. 5 (2025): e2412222.

[35] A. D. S. Pathare and I. Hinduja, “Endometrial Expression of Cell Adhesion Genes in Recurrent Implantation Failure Patients in Ongoing IVF Cycle,” Reproductive Sciences 29, no. 2 (2022): 513–523.

[36] M. Y. Turco, L. Gardner, J. Hughes, et al., “Long-Term, Hormone-Responsive Organoid Cultures of Human Endometrium in a Chemically Defined Medium,” Nature Cell Biology 19, no. 5 (2017): 568–577.

[37] W. Dai, G. Wu, K. Liu, et al., “Lactate Promotes Myogenesis via Activating H3K9 Lactylation-Dependent Up-Regulation of Neu2 Expression,” Journal of Cachexia, Sarcopenia and Muscle 14, no. 6 (2023): 2851–2865.

[38] J. Li, W. Hou, Q. Zhao, et al., “Lactate Regulates Major Zygotic Genome Activation by H3K18 Lactylation in Mammals,” National Science Review 11, no. 2 (2024): nwad295.

[39] P. Chen, X. Li, R. Zhang, et al., “Combinative Treatment of Beta-Elemene and Cetuximab Is Sensitive to KRAS Mutant Colorectal Cancer Cells by Inducing Ferroptosis and Inhibiting Epithelial–Mesenchymal Transformation,” Theranostics 10, no. 11 (2020): 5107–5119.

[40] J. M. Yu, W. Sun, F. Hua, et al., “BCL6 Induces EMT by Promoting the ZEB1-Mediated Transcription Repression of E-Cadherin in Breast Cancer Cells,” Cancer Letters 365, no. 2 (2015): 190–200.

[41] W. Luan, Y. Ding, H. Xi, et al., “Exosomal miR-106b-5p Derived From Melanoma Cell Promotes Primary Melanocytes Epithelial–Mesenchymal Transition Through Targeting EphA4,” Journal of Experimental & Clinical Cancer Research 40, no. 1 (2021): 107.

[42] Y. Yi, Z. Yang, C. Zhou, Y. Yang, Y. Wu, and Q. Zhang, “Quercetin-Encapsulated GelMa Hydrogel Microneedle Reduces Oxidative Stress and Facilitates Wound Healing,” Nano TransMed 3 (2024): 100030.

[43] T. Hiraoka, Y. Osuga, and Y. Hirota, “Current Perspectives on Endometrial Receptivity: A Comprehensive Overview of Etiology and Treatment,” Journal of Obstetrics and Gynaecology Research 49, no. 10 (2023): 2397–2409.

[44] X. Li, Y. Yang, B. Zhang, et al., “Lactate Metabolism in Human Health and Disease,” Signal Transduction and Targeted Therapy 7, no. 1 (2022): 305.

[45] X. Hu, Y. Tang, W. Zhao, et al., “Lactate Promotes the Second Cell Fate Decision in Blastocysts by Prompting Primitive Endoderm Formation Through an Intercellular Positive Feedback Loop That Couples Paracrine FGF Signalling,” Cell Proliferation 58 (2025): e70088.

[46] F. Oghbaei, R. Zarezadeh, D. Jafari-Gharabaghlou, et al., “Epithelial–Mesenchymal Transition Process During Embryo Implantation,” Cell and Tissue Research 388, no. 1 (2022): 1–17.

[47] J. Liu, Y. Li, R. Ma, et al., “Cold Atmospheric Plasma Drives USP49/HDAC3 Axis Mediated Ferroptosis as a Novel Therapeutic Strategy in Endometrial Cancer via Reinforcing Lactylation Dependent p53 Expression,” Journal of Translational Medicine 23, no. 1 (2025): 442.

[48] Z. Liang, J. Liu, Y. Gou, et al., “Elevated Histone Lactylation Mediates Ferroptosis Resistance in Endometriosis Through the METTL3-Regulated HIF1A/HMOX1 Signaling Pathway,” Advancement of Science 12 (2025): e08220.

[49] X. Liu, Y. Zhang, L. Zhuang, K. Olszewski, and B. Gan, “NADPH Debt Drives Redox Bankruptcy: SLC7A11/xCT-Mediated Cystine Uptake as a Double-Edged Sword in Cellular Redox Regulation,” Genes & Diseases 8, no. 6 (2021): 731–745.

[50] Y. Li, H. Zhang, F. Yang, et al., “Mechanisms and Therapeutic Potential of Disulphidptosis in Cancer,” Cell Proliferation 58, no. 1 (2025): e13752.

[51] P. Koppula, L. Zhuang, and B. Gan, “Cystine Transporter SLC7A11/xCT in Cancer: Ferroptosis, Nutrient Dependency, and Cancer Therapy,” Protein & Cell 12, no. 8 (2021): 599–620.

[52] Y. D. Bhutia, J. Ogura, P. J. Grippo, et al., “Chronic Exposure to Excess Iron Promotes EMT and Cancer via p53 Loss in Pancreatic Cancer,” Asian Journal of Pharmaceutical Sciences 15, no. 2 (2020): 237–251.

[53] P. Koppula, Y. Zhang, L. Zhuang, and B. Gan, “Amino Acid Transporter SLC7A11/xCT at the Crossroads of Regulating Redox Homeostasis and Nutrient Dependency of Cancer,” Cancer Communications 38, no. 1 (2018): 12.

[54] N. Zhou, J. Chen, M. Hu, et al., “SLC7A11 Is an Unconventional H(+) Transporter in Lysosomes,” Cell 188, no. 13 (2025): 3441–3458.e3425.

[55] G. Yang, G. Yao, H. Wang, et al., “Melatonin Affects Trophoblast Epithelial-to-Mesenchymal Transition and Oxidative Damage Resistance by Modulating GDF15 Expression to Promote Embryo Implantation,” Communications Biology 8, no. 1 (2025): 396.

[56] P. Wang, S. Du, C. Guo, et al., “The Presence of Blastocyst Within the Uteri Facilitates Lumenal Epithelium Transformation for Implantation via Upregulating Lysosome Proteostasis Activity,” Autophagy 20, no. 1 (2024): 58–75.

[57] J. G. Cheng, J. R. Chen, L. Hernandez, W. G. Alvord, and C. L. Stewart, “Dual Control of LIF Expression and LIF Receptor Function Regulate Stat3 Activation at the Onset of Uterine Receptivity and Embryo Implantation,” Proceedings of the National Academy of Sciences of the United States of America 98, no. 15 (2001): 8680–8685.

[58] D. Siriwardena and T. E. Boroviak, “Evolutionary Divergence of Embryo Implantation in Primates,” Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences 377, no. 1865 (2022): 20210256.

[59] J. R. Canizo, C. Zhao, and S. Petropoulos, “The Guinea Pig Serves as an Alternative Model to Study Human Preimplantation Development,” Nature Cell Biology 27, no. 4 (2025): 696–710.

[60] B. Yin, X. Cui, Y. Liu, and J. F. Fei, “Salamanders Aid Research Into Mechanisms of Non-Canonical Organ Regeneration for Clinical Applications,” Medicine Advances 2, no. 2 (2024): 101–111.

[61] S. Matsumoto and N. Yamamoto, “Acceptance of Encapsulated Porcine Islet Xenotransplantation by Patients and Doctors in the US,” Medicine Advances 1, no. 3 (2023): 210–218.

RIGHTS & PERMISSIONS

2025 The Author(s). Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.