Glycolytic reprogramming in endometriosis: molecular mechanisms, immune modulation, and non-hormonal therapeutic opportunities

Guo L, Lijuan Guo, Lanqing Liu, Liu L, Yu Geng, Geng Y, Bing Zhang, Zhang B, Zhao S, Shaojie Zhao
BMC women's health · 2026 · vol. 26(1) · doi:10.1186/s12905-026-04570-4 · PMID:42186039 · PMC13386883 · W7162304929
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⚙ AI-generated summary by gemini-2.5-flash-lite, 2026-06-08 ⓘ

This review synthesizes research on how enhanced aerobic glycolysis drives endometriosis pathogenesis through specific enzyme upregulation and immune modulation, highlighting therapeutic opportunities in glycolysis inhibitors.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-08 · read from full text ⓘ

This narrative review focuses on how metabolic reprogramming toward aerobic glycolysis (the Warburg effect) contributes to endometriosis lesion development, integrating evidence on altered expression of glycolytic enzymes such as HK2, PFKFB3, and PKM2 via signaling pathways including ALKBH5–HK2, PAK5–PKM2, and S1PR4/mTOR. It reports that increased glycolytic flux and lactate accumulation can promote proliferation, invasion, and epithelial–mesenchymal transition while shaping an immunosuppressive microenvironment through mechanisms such as M2 macrophage polarization and histone lactylation. The review also evaluates emerging non-hormonal approaches targeting glycolysis, and discusses how immune-metabolic gene signatures may aid non-invasive diagnosis, while acknowledging that it synthesizes existing studies rather than presenting new experimental results. This paper is centrally about endometriosis — it reviews glycolytic reprogramming mechanisms, immune modulation, and non-hormonal therapeutic opportunities in endometriosis.

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Abstract

Endometriosis is a chronic gynecological disorder characterized by ectopic tissue growth and significant morbidity, yet current hormonal and surgical treatments often fail to prevent recurrence or entail severe side effects. Increasing evidence highlights metabolic reprogramming, specifically aerobic glycolysis (the Warburg effect), as a fundamental driver of endometriotic lesion pathogenesis. This narrative review synthesizes current research on the regulatory mechanisms and therapeutic potential of targeting glycolytic dysregulation in endometriosis. We examine the aberrant upregulation of rate-limiting enzymes, including hexokinase 2 (HK2), 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), and pyruvate kinase M2 (PKM2), driven by signaling axes such as ALKBH5-HK2, PAK5-PKM2, and S1PR4/mTOR. The review further elucidates how enhanced glycolytic flux and lactate accumulation promote cell proliferation, invasion, and epithelial-mesenchymal transition (EMT) while orchestrating an immunosuppressive microenvironment via M2 macrophage polarization and histone lactylation. Furthermore, we evaluate emerging non-hormonal therapeutic strategies, including specific glycolysis inhibitors and natural compounds, and discuss the utility of immune-metabolic gene signatures for non-invasive diagnosis. Highlighting these metabolic vulnerabilities offers promising avenues for precision medicine to improve clinical management and patient outcomes in endometriosis.
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Abstract

Endometriosis is a chronic gynecological disorder characterized by ectopic tissue growth and significant morbidity, yet current hormonal and surgical treatments often fail to prevent recurrence or entail severe side effects. Increasing evidence highlights metabolic reprogramming, specifically aerobic glycolysis (the Warburg effect), as a fundamental driver of endometriotic lesion pathogenesis. This narrative review synthesizes current research on the regulatory mechanisms and therapeutic potential of targeting glycolytic dysregulation in endometriosis. We examine the aberrant upregulation of rate-limiting enzymes, including hexokinase 2 (HK2), 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), and pyruvate kinase M2 (PKM2), driven by signaling axes such as ALKBH5–HK2, PAK5–PKM2, and S1PR4/mTOR. The review further elucidates how enhanced glycolytic flux and lactate accumulation promote cell proliferation, invasion, and epithelial–mesenchymal transition (EMT) while orchestrating an immunosuppressive microenvironment via M2 macrophage polarization and histone lactylation. Furthermore, we evaluate emerging non-hormonal therapeutic strategies, including specific glycolysis inhibitors and natural compounds, and discuss the utility of immune-metabolic gene signatures for non-invasive diagnosis. Highlighting these metabolic vulnerabilities offers promising avenues for precision medicine to improve clinical management and patient outcomes in endometriosis. Similar content being viewed by others Abbreviations - 2-DG: - 2-Deoxy-D-glucose - ALKBH5: - AlkB Homolog 5 - AURKA: - Aurora Kinase A - CD47: - Cluster of Differentiation 47 - CHIP: - STIP1 Homology and U-box Containing Protein 1 - CGRP: - Calcitonin Gene-Related Peptide - EMT: - Epithelial–Mesenchymal Transition - ERβ: - Estrogen Receptorβ - HIF-1α: - Hypoxia-Inducible Factor-1α - HK2: - Hexokinase 2 - HMGB1: - High Mobility Group Box 1 - LDHA: - Lactate Dehydrogenase A - m6A: - N6-methyladenosine - MCT1: - Monocarboxylate Transporter 1 - MDSC: - Myeloid-Derived Suppressor Cells - mTOR: - Mammalian Target of Rapamycin - PAK5: - P21-Activated Kinase 5 - PDCD1: - Programmed Cell Death Protein 1 - PDPK1: - 3-Phosphoinositide-Dependent Protein Kinase 1 - PFKFB3/4: - 6-Phosphofructo-2-Kinase/Fructose-2,6-Bisphosphatase 3/4 - PIM2: - Proviral Integration Site for Moloney Murine Leukemia Virus 2 - PKM2: - Pyruvate Kinase M2 - RAMP1: - Receptor Activity-Modifying Protein 1 - ROS: - Reactive Oxygen Species - S1PR4: - Sphingosine-1-Phosphate Receptor 4 - STAT1: - Signal Transducer and Activator of Transcription 1

Acknowledgements

The authors thank Figdraw platform for providing graphics-related help. Funding This work was supported by Wuxi Taihu Talent Medical Team, Wuxi Medical Development Discipline (FZXK2021008), and Elite Talent Project of Wuxi Maternity and Child Care Healthy Hospital of Jiangnan University (LY2023004). Author information Authors and Affiliations Corresponding authors Ethics declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Competing interests The authors declare no competing interests. Additional information Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Rights and permissions Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/. About this article Cite this article Guo, L., Liu, L., Geng, Y. et al. Glycolytic reprogramming in endometriosis: molecular mechanisms, immune modulation, and non-hormonal therapeutic opportunities. BMC Women's Health (2026). https://doi.org/10.1186/s12905-026-04570-4 Received: Accepted: Published: DOI: https://doi.org/10.1186/s12905-026-04570-4

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endometriosis

MeSH descriptors

Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis

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chemicals 1
lactate

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