Ferroptosis-associated macrophages suggest a potential ACSL1-PGE2-stromal iron homeostasis-related axis in endometriosis

Jingyi Wang, Mengting Liu, Xianchen Luo, Yan Zhang, Jin Ding
Molecular biology reports · 2026 · vol. 53(1) · doi:10.1007/s11033-026-13044-7 · PMID:43007482
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Abstract

BACKGROUND: Endometriosis (EMs) is characterized by chronic inflammation, recurrent bleeding, oxidative stress, and disrupted local iron homeostasis. Although macrophages are important components of the immune microenvironment in EMs, their ferroptosis-related heterogeneity and potential association with iron homeostasis remain unclear. This study investigated ferroptosis-associated macrophages (FAMs) and their potential involvement in immune-iron homeostasis coupling in EMs. METHODS: Publicly available single-cell RNA sequencing data were used to characterize macrophage heterogeneity in eutopic endometrial samples from women with EMs and disease-free controls. Differential expression, functional enrichment, donor-level, pseudobulk, pseudotime ordering, and inferred cell-cell communication analyses, together with independent bulk RNA sequencing, were used to prioritize candidate regulators. In vitro experiments included ferroptosis-related phenotype induction, ACSL1 knockdown, PGE2 quantification, EP2 receptor blockade, and iron-loading and chelation assays. RESULTS: FAMs were preferentially enriched in the EMs group and exhibited elevated ferroptosis-related transcriptional activity. Integrative transcriptomic and donor-level analyses supported the prioritization of acyl-CoA synthetase long-chain family member 1 (ACSL1) as a candidate metabolic regulator. Ferrostatin-1 treatment significantly attenuated erastin-induced lipid peroxidation and cellular injury. ACSL1 knockdown markedly attenuated ferroptosis-related alterations and PGE2 secretion in macrophages. In endometriotic stromal cells, PGE2 treatment downregulated FTH1 expression, upregulated SLC40A1 expression, and elevated extracellular Fe³⁺ levels; these changes were partially reversed by EP2 receptor blockade. Iron chelation treatment significantly attenuated FAC-induced lipid peroxidation and cellular injury in macrophages. CONCLUSION: The findings support a proposed macrophage-stromal interaction axis linking ACSL1-PGE2-associated signaling, stromal iron homeostasis-related changes, and extracellular iron loading, with potential intervention points involving ACSL1, PGE2/EP2 signaling, and iron homeostasis.

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MeSH descriptors

Coenzyme A Ligases Coenzyme A Ligases Coenzyme A Ligases Dinoprostone Dinoprostone Endometriosis Endometriosis Endometriosis Endometriosis Ferroptosis Ferroptosis Ferroptosis Iron Iron Macrophages Macrophages Adult Endometrium Endometrium Female

Funding

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[{'doi': None, 'name': 'the 2025 Anhui Provincial Health Research Project', 'awards': ['Grant No. YL-2026-13']}, {'doi': None, 'name': 'he National Natural Science Foundation of China', 'awards': ['Grant No. 82201820']}, {'doi': None, 'name': 'the 2024 Young and Middle-aged Teacher Training Action Project of Anhui Province', 'awards': ['Project No. YQZD2024030']}, {'doi': None, 'name': 'Anhui Provincial Research Project', 'awards': ['Project No. 202427b10020092']}]

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References (46)

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