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Peer-reviewedCC BYBMC Medicine

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

  • Ming Yuan1
  • Xue Jiao1
  • Le Xu1
  • Shuang Wang2
  • Lei Yan3
  • Zhaoyang Zhong2
  • Qianhui Ren1
  • Xiaoyu Dong1
  • Hongwei Guan1
  • Na Li1
  • Chunyan Li1
  • Jing Zhao1
3 more authors
  • Kun Liu1
  • Xiaoli Meng4
  • Guoyun Wang1
4 affiliations
  1. 1Department of Obstetrics and Gynecology, Shandong Provincial Hospital Affiliated to Shandong First Medical University
  2. 2Shandong Key Laboratory of Reproductive Research and Birth Defect Prevention, Shandong First Medical University
  3. 3Medical Integration and Practice Center, Cheeloo College of Medicine, Shandong University
  4. 4Lc-Bio Technologies (Hangzhou) Co.,Ltd
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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

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Cite

BibTeXRIS
BibTeX
@article{yuan2026ionomics,
  title = {{Ionomics powered single-cell mapping reveals targetable iron dysregulation in endometriosis associated macrophages}},
  author = {Ming Yuan and Xue Jiao and Le Xu and Shuang Wang and Lei Yan and Zhaoyang Zhong and Qianhui Ren and Xiaoyu Dong and Hongwei Guan and Na Li and Chunyan Li and Jing Zhao and Kun Liu and Xiaoli Meng and Guoyun Wang},
  journal = {BMC Medicine},
  year = {2026},
  month = jul,
  doi = {10.1186/s12916-026-05095-1},
  url = {https://doi.org/10.1186/s12916-026-05095-1},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Ionomics powered single-cell mapping reveals targetable iron dysregulation in endometriosis associated macrophages
AU  - Ming Yuan
AU  - Xue Jiao
AU  - Le Xu
AU  - Shuang Wang
AU  - Lei Yan
AU  - Zhaoyang Zhong
AU  - Qianhui Ren
AU  - Xiaoyu Dong
AU  - Hongwei Guan
AU  - Na Li
AU  - Chunyan Li
AU  - Jing Zhao
AU  - Kun Liu
AU  - Xiaoli Meng
AU  - Guoyun Wang
PY  - 2026
DA  - 2026/07/01
JO  - BMC Medicine
DO  - 10.1186/s12916-026-05095-1
UR  - https://doi.org/10.1186/s12916-026-05095-1
AB  - 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
SN  - 1741-7015
ER  -