Inflammation–fibrosis crosstalk in endometriosis: immune–stromal mechanisms linking lesion persistence to pain and infertility

Xiaofeng Liu, Zheng Qu, Jinhong Gu, Fang Lian, Shuguang Fu
In: Frontiers in Medicine · 2026 · vol. 13 · doi:10.3389/fmed.2026.1984591 · W7214914029
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Abstract

Endometriosis is an estrogen-dependent chronic inflammatory disorder in which ectopic endometrial-like tissue undergoes repeated injury, incomplete resolution, and progressive remodeling. Fibrosis is therefore not merely a terminal scar but an active component of lesion biology. Cyclic bleeding activates platelets and innate immune cells, generates iron-dependent oxidative stress and hypoxia, and sustains transforming growth factor-β, sphingosine-1-phosphate, Wnt/β-catenin, PI3K/AKT–ERK, and Notch-related signals. These cues promote fibroblast activation, myofibroblast differentiation, extracellular-matrix deposition, and epithelial-, endothelial-, mesothelial-, or macrophage-to-mesenchymal plasticity. The resulting stiff matrix can further reinforce inflammatory, vascular, and neural programs, creating a self-maintaining inflammation–fibrosis circuit. Clinically, this circuit may stabilize ectopic lesions, promote adhesions, increase tissue tension and neurogenic inflammation, damage the ovarian cortex, and perturb the peritoneal and eutopic endometrial environments. These effects provide mechanistic links to persistent pain and infertility, although fibrosis is neither the sole determinant of symptoms nor a uniform feature across lesion phenotypes. This Mini Review integrates evidence from experimental models, human pathology, and single-cell studies; identifies uncertainties in cellular lineage, lesion chronology, and outcome attribution; and discusses therapeutic implications. Conventional hormonal and surgical treatment remains central, whereas antifibrotic, immunomodulatory, and complementary approaches require mechanism-based clinical validation. Progress will depend on standardized fibrosis phenotyping, longitudinal and spatial sampling, patient-derived multicellular models, and trials that align biological targets with pain, fertility, and recurrence outcomes.

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