Metabolic-epigenetic imprinting of macrophages in endometriosis: a working model for lesion persistence and treatment.

Endometriosis is an estrogen-dependent inflammatory disorder that often persists or returns even after visible lesions have been removed. The behavior of peritoneal macrophages may help explain this clinical durability. These cells participate in lesion implantation, vascularization, fibrosis, defective immune clearance, and pain, but it is uncertain why disease-supporting phenotypes are maintained. We argue that repeated exposure to the endometriotic niche may leave macrophages with a metabolically conditioned epigenetic memory rather than only a short-lived polarization state. Lactate, succinate, iron, oxysterols, and glutamine-derived metabolites could alter cellular metabolism while also providing substrates, cofactors, or inhibitors for chromatin-modifying enzymes. Histone lactylation and TET/JmjC-regulated methylation states are plausible molecular records of this exposure, although neither has yet been followed from metabolite to persistent mark and macrophage function in human disease. At present, the most direct endometriosis-specific support comes from a TGF-β1/CCL2-induced TET3 program associated with let-7 repression, inflammatory cytokine production, and macrophage survival. Other proposed circuits, including lactate-lactylation coupling and macrophage-stromal exchange of glycolytic signals, remain incomplete. This distinction matters: established findings support parts of the model, but not yet the entire causal chain. A memory state should be experimentally identifiable by its persistence after stimulus withdrawal, transferability, metabolic dependence, and reversibility. If experiments satisfy these criteria, the retained macrophage state would become a plausible non-hormonal target. The relevant test would be whether changing that state produces a lasting loss of lesion-supporting function instead of a brief reduction in downstream inflammation.