Ionomics powered single-cell mapping reveals targetable iron dysregulation in endometriosis associated macrophages

Yuan M, Ming Yuan, Jiao X, Xue Jiao, Le Xu, Xu L, S Wang, Wang S, Shuang Wang, Lei Yan, Yan L, Zhaoyang Zhong, Zhong Z, Qianhui Ren, Ren Q, Xiaoyu Dong, Dong X, Guan H, Hongwei Guan, Na Li, Li N, C S Li, Chunyan Li, Li C, Jing Zhao, Zhao J, Liu K, Kun Liu, Xiaoli Meng, Meng X, Guoyun Wang, Wang G
BMC medicine · 2026 · vol. 24(1) · doi:10.1186/s12916-026-05095-1 · PMID:42920128 · PMC13693042 · W7171454730
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This study found that iron dysregulation in endometriotic macrophages, driven by senescent red blood cell phagocytosis, promotes immunosuppression and ectopic lesion growth, suggesting macrophage iron metabolism as a therapeutic target.

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This study utilized inductively coupled plasma mass spectrometry and single-cell RNA sequencing to characterize the elemental landscape and cellular subpopulations within endometriotic cyst fluid. The researchers identified iron as the most significantly elevated element and found that macrophages in these lesions exhibited an immunosuppressive M2-like phenotype driven by iron overload from senescent red blood cells. Mechanistically, this iron accumulation triggered ferroptosis-related stress and impaired phagocytic capacity, which suppressed CD8+ T and NK cell functions via the CXCL12-CXCR4 axis, while animal models showed that iron chelation and ferroptosis inhibition could reduce lesion growth. This paper is centrally about endometriosis — specifically focusing on the role of iron dysregulation and macrophage polarization in disease progression.

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Abstract

BACKGROUND: Endometriosis affects approximately 10% of women of reproductive age worldwide. Although elemental components of refluxed menstrual blood have been implicated in disease progression, comprehensive ionomic profiling of the endometriotic microenvironment remains limited. Characterizing the localized elemental landscape may generate new hypotheses regarding disease mechanisms. METHODS: We employed inductively coupled plasma mass spectrometry (ICP-MS) to profile 63 elements in endometriotic cyst fluid. Single-cell RNA sequencing (scRNA-seq) was performed to explore cellular subpopulations potentially associated with elemental dysregulation. Senescent red blood cells (sRBCs) were used to model retrograde menstruation in endometriosis. The effects of iron chelation with deferoxamine (DFO) and ferroptosis inhibition with ferrostatin-1 (Fer-1) were evaluated. RESULTS: ICP-MS identified iron as the most significantly elevated element in patients with endometriosis, supported by flow cytometry and Prussian blue staining. ScRNA-seq revealed a macrophage subcluster enriched in endometriotic lesions, co-expressing M2-associated markers and ferroptosis-related genes. Mechanistically, sRBC phagocytosis activated HIF-1α and HO-1 expression in macrophages, accompanied by intracellular iron accumulation, sublethal ferroptotic stress characterized by elevated lipid peroxidation and reactive oxygen species, M2-like polarization, and impaired phagocytic capacity. These iron-laden macrophages suppressed CD8+ T and NK cell effector functions, at least in part through the CXCL12-CXCR4 signaling axis. In the mouse model, treatment with DFO and Fer-1 partly reversed macrophage polarization, restored phagocytic function, alleviated lymphocyte suppression, and reduced ectopic lesion growth. CONCLUSIONS: This exploratory study suggests that sRBC-derived iron overload may be associated with a shift of macrophages toward an immunosuppressive phenotype, potentially linked to the HIF-1α/HO-1/GPX4 pathway. These changes may contribute to local immune dysfunction in endometriosis. These findings highlight macrophage iron metabolism as a potential therapeutic target that warrants validation in larger and independent cohorts.
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Abstract

Background Endometriosis affects approximately 10% of women of reproductive age worldwide. Although elemental components of refluxed menstrual blood have been implicated in disease progression, comprehensive ionomic profiling of the endometriotic microenvironment remains limited. Characterizing the localized elemental landscape may generate new hypotheses regarding disease mechanisms.

Methods

We employed inductively coupled plasma mass spectrometry (ICP-MS) to profile 63 elements in endometriotic cyst fluid. Single-cell RNA sequencing (scRNA-seq) was performed to explore cellular subpopulations potentially associated with elemental dysregulation. Senescent red blood cells (sRBCs) were used to model retrograde menstruation in endometriosis. The effects of iron chelation with deferoxamine (DFO) and ferroptosis inhibition with ferrostatin-1 (Fer-1) were evaluated.

Results

ICP-MS identified iron as the most significantly elevated element in patients with endometriosis, supported by flow cytometry and Prussian blue staining. ScRNA-seq revealed a macrophage subcluster enriched in endometriotic lesions, co-expressing M2-associated markers and ferroptosis-related genes. Mechanistically, sRBC phagocytosis activated HIF-1α and HO-1 expression in macrophages, accompanied by intracellular iron accumulation, sublethal ferroptotic stress characterized by elevated lipid peroxidation and reactive oxygen species, M2-like polarization, and impaired phagocytic capacity. These iron-laden macrophages suppressed CD8+ T and NK cell effector functions, at least in part through the CXCL12-CXCR4 signaling axis. In the mouse model, treatment with DFO and Fer-1 partly reversed macrophage polarization, restored phagocytic function, alleviated lymphocyte suppression, and reduced ectopic lesion growth.

Conclusions

This exploratory study suggests that sRBC-derived iron overload may be associated with a shift of macrophages toward an immunosuppressive phenotype, potentially linked to the HIF-1α/HO-1/GPX4 pathway. These changes may contribute to local immune dysfunction in endometriosis. These findings highlight macrophage iron metabolism as a potential therapeutic target that warrants validation in larger and independent cohorts. Graphical abstract Similar content being viewed by others Abbreviations - ICP-MS: - inductively coupled plasma mass spectrometry - HO-1: - heme oxygenase 1 - scRNA-seq: - Single-cell RNA sequencing - FBS: - fetal bovine serum - UMAP: - Uniform manifold approximation and projection - KEGG: - Kyoto Encyclopedia of Genes and Genomes - BMDM: - Bone marrow derived macrophage - DEGs: - differentially expressed genes - RBC: - red blood cell - sRBC: - senescent RBC - DFO: - Deferoxamine - Fer-1: - ferrostatin-1 - rASRM: - revised American Society for Reproductive Medicine - DMEM/F-12: - Dulbecco’s modified Eagle’s medium/F12 medium - PCA: - principal component analysis - CPDA: - citrate phosphate dextrose adenine - DMEM: - Dulbecco’s Modified Eagle Medium - ZnPP: - zinc protoporphyrin - PMSF: - phenylmethanesulfonyl fluoride - HIF-1α: - hypoxia-inducible factor 1 subunit alpha - MESCs: - mouse endometrial stromal cells - CA125: - cancer antigen 125 - ROS: - reactive oxygen species - LPO: - lipid peroxidation

Acknowledgements

We thank the Translational Medicine Core Facility of Shandong University for consultation and instrument availability that supported this work. Thanks to Figdraw for providing the graphic platform. Funding This research was supported from the National Key R&D Program of China (2023YFC2705405), the Special foundation for Taishan Scholars (No. tstp20230657), and the National Natural Science Foundation of China (grant numbers 82371653 and 82301855). Author information Authors and Affiliations Corresponding author Ethics declarations Ethics approval and consent to participate Mice were handled in accordance with the Guide for the Care of Laboratory Animals and all procedures were approved by the Ethics Committee of Medical Integration and Practice Center of Shandong University (SDULCLL2022-2-17; approval date: 4 November 2022). The study was approved by the Ethics Committee of Medical Integration and Practice Center of Shandong University (SDULCLL2022-1-21; approval date: 4 November 2022), and all patients provided written informed consent. 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. Supplementary Information Below is the link to the electronic supplementary material. 12916_2026_5095_MOESM3_ESM.xlsx (download XLSX ) Supplementary Material 3: Additional file 3: ICP-MS elemental profiling data from the preliminary screening cohort (Endo, n = 6; Ctrl, n = 6) 12916_2026_5095_MOESM4_ESM.xlsx (download XLSX ) Supplementary Material 4: Additional file 4: ICP-MS elemental profiling data from the validation cohort (Endo, n = 23; Ctrl, n = 12) 12916_2026_5095_MOESM6_ESM.xlsx (download XLSX ) Supplementary Material 6: Additional file 6: The supplementary table listing the significantly upregulated genes in C5 compared to other macrophage clusters 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 Yuan, M., Jiao, X., Xu, L. et al. Ionomics powered single-cell mapping reveals targetable iron dysregulation in endometriosis associated macrophages. BMC Med (2026). https://doi.org/10.1186/s12916-026-05095-1 Received: Accepted: Published: DOI: https://doi.org/10.1186/s12916-026-05095-1

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MeSH descriptors

Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Iron Iron Iron Iron Iron Iron Iron Iron

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References (55)

SciLite annotations

chemicals 12
iron iron desferrioxamine ferrostatin-1 iron brilliant blue iron lipid oxygen iron iron iron
organisms 1
transgenic mice

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