Endometriosis Has a Metabolism Problem, and Targeting It Could Transform Treatment

A new review published in the Journal of Advanced Research makes the case that endometriosis is fundamentally a metabolism problem, one in which ectopic cells rewire their energy systems to survive, spread, evade the immune system, and impair fertility in ways that hormonal suppression cannot reverse.¹ The authors state that this metabolic reprogramming is not just a side effect of endometriosis, but a core engine of disease progression. By synthesizing data from preclinical cellular and animal studies, human tissue analyses, multi-omics studies (including single-cell transcriptomics, spatial metabolomics, and lipidomics), and early-phase clinical trials, the analysis systematically maps 3 major metabolic shifts in endometriosis, traces how each one feeds the disease, and surveys an emerging landscape of targeted therapies that could finally move treatment beyond hormones.

Glucose, Lipids, and Amino Acids

Ectopic endometrial cells in endometriosis undergo extensive metabolic rewiring across 3 interconnected pathways. In glucose metabolism, cells shift dramatically toward aerobic glycolysis, mirroring the Warburg effect seen in cancer. Here, cells upregulate glucose uptake and glycolytic enzymes while suppressing oxidative phosphorylation. The accumulated lactate here is more than a metabolic waste product, as it drives histone lactylation that reshapes gene expression, promotes immune-suppressive M2 macrophage polarization, exhausts CD8⁺ T cells, and induces fibrosis and epithelial-mesenchymal transition, creating a self-reinforcing cycle in which glycolysis sustains the very microenvironment that protects the lesion. Lipid metabolism is equally disrupted as the sphingolipid balance tips away from pro-apoptotic ceramide and toward mitogenic glucosylceramide. Sphingosine-1-phosphate (S1P) accumulates to drive inflammation, angiogenesis, and further macrophage polarization. A separate cholesterol-estrogen feedback loop elevates local estradiol through steroidogenic enzyme activation, then suppresses cholesterol efflux to sustain its own signaling, fueling ectopic cell proliferation in a manner largely independent of systemic hormone levels and offering a mechanistic explanation for why hormonal therapies so frequently fall short. Lastly, the amino acid metabolism is also disrupted. Tryptophan is converted to kynurenine, activating the aryl hydrocarbon receptor to suppress cytotoxic T cells and expand regulatory T cells, with estrogen amplifying this immunosuppressive axis further. Simultaneously, elevated glutaminolysis compensates for pyruvate's diversion away from the TCA cycle, sustaining biosynthetic demands and, through the proline-glutamine axis, promoting the lesion fibrosis that makes the disease so difficult to eradicate surgically.

Metabolic Crosstalk: An Integrated Vicious Cycle

Endometriosis affects roughly 10% of women of reproductive age worldwide and is responsible for infertility in up to 50% of women struggling to conceive. The review states that these 3 metabolic domains may be associated with endometriosis-associated infertility. Granulosa cells from patients with endometriosis show enhanced glycolysis, mitochondrial dysfunction, ceramide accumulation, and iron overload. These changes matter because oocytes depend almost entirely on granulosa cells for energy and antioxidant support. When granulosa cell metabolism fails, oocytes are exposed to oxidative stress and acidic conditions, resulting in meiotic arrest, spindle abnormalities, and impaired maturation. Follicular fluid metabolomics in endometriosis patients reflects this dysfunction directly, with reduced glucose and citrate, elevated lactate, and markedly decreased 14,15-epoxyeicosatrienoic acid, which is a finding associated with granulosa cell senescence and poor assisted reproductive technology outcomes. This granulosa cell-mediated mechanism reframes infertility in endometriosis not as collateral damage from pelvic inflammation, but as a direct consequence of localized metabolic disease that may be amenable to targeted intervention.

Reframing Endometriosis as a Metabolic Disease

This review reframes endometriosis as a metabolic disease in which the characteristic behaviors of ectopic tissue such as invasion, immune evasion, angiogenesis, fibrosis, and recurrence emerge not just from hormonal dysregulation but from a deeply altered cellular metabolism that current treatments do not address.

The clinical significance of this framing is substantial. It suggests that patient stratification by metabolic subtype could guide treatment selection. For example, Sodium dichloroacetate (DCA) or PFKFB inhibitors may be most appropriate for glycolysis-dominant patients without fertility needs, whereas IDO1 inhibitors could offer dual benefit for patients with both infertility and tryptophan pathway dysregulation. A 2023 study demonstrated that endometriosis primarily impairs oocyte quality through granulosa cell dysfunction rather than direct oocyte damage, which aligns with this review's finding that granulosa cell metabolic reprogramming is a discrete and potentially targetable mechanism in endometriosis-associated infertility.²

This metabolic lens also opens new possibilities in assisted reproduction. Metabolomic profiling of follicular fluid, which captures the local ovarian metabolic environment far more directly than serum, could yield biomarkers for oocyte and embryo quality that go beyond morphology. Interventions such as 14,15-epoxyeicosatrienoic acid (EET) supplementation (which suppresses specific granulosa cell senescence in preclinical work) or iron chelation could potentially be incorporated into ovarian stimulation protocols.

The field's near-term needs are clear: better preclinical models (patient-derived organoids, humanized immune system mouse models), integrative multiomics platforms linking spatial metabolomics to single-cell transcriptomics, real-time metabolic imaging to monitor therapeutic response, and clinical trials that enroll patients stratified by metabolic phenotype rather than treating endometriosis as a homogeneous condition.

Combination strategies such as pairing metabolic inhibitors with immunotherapy, anti-angiogenic agents, or traditional hormonal therapies may also prove more effective than single-pathway approaches, particularly given the metabolic plasticity ectopic cells display under therapeutic pressure.

Overall, the review states that endometriosis is no longer just a hormonal disease. The growing evidence establishes metabolic reprogramming across glucose, lipid, and amino acid pathways is a central and mechanistically coherent driver of endometriosis pathology. Lactate drives epigenetic and immune remodeling. Cholesterol fuels a hyperestrogenic niche. Tryptophan catabolism dismantles immune surveillance. And in the ovary, this metabolic disorder cascades into granulosa cell dysfunction that degrades oocyte quality and contributes to infertility. For a disease affecting tens of millions of women worldwide, this metabolic framework may provide the biological foundation for that next generation of treatment.

References

1. Guo C, Na X, Guo Z, et al. Metabolic reprogramming in endometriosis: mechanisms and therapeutic prospects. J Adv Res. Published online May 3, 2026. doi:10.1016/j.jare.2026.04.069
2. Fan W, Yuan Z, Li M, Zhang Y, Nan F. Decreased oocyte quality in patients with endometriosis is closely related to abnormal granulosa cells. Front Endocrinol (Lausanne). 2023;14:1226687. doi:10.3389/fendo.2023.1226687