Macrophages originated IL-33/ST2 inhibits ferroptosis in endometriosis via the ATF3/SLC7A11 axis

Qiong Wu, Zongwen Liang, Jing Jiang, Xiaoming Feng, Jinming Liu, Zongfeng Zhang, Honglin Wang, Ning Wang, Yanling Gou, Zhi Li, Yingying Cao
Cell death & disease · 2023 · vol. 14(10) , pp. 668 · doi:10.1038/s41419-023-06182-4 · PMID:37816731 · PMC10564909 · W4387477698
article OA: gold CC0 ⤵ 42 in-corpus citations
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⚙ AI-generated summary by claude@2026-06, 2026-06-08 ⓘ

Macrophages secrete IL-33/ST2, which suppresses ferroptosis in endometriosis by downregulating ATF3 and upregulating SLC7A11 via the P38/JNK pathway, thereby promoting eESC viability and migration.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-09 ⓘ

This paper investigated how macrophage-derived IL-33 regulates ectopic endometrial stromal cells (eESCs) by focusing on ferroptosis, using co-culture experiments and IL-33/ST2 stimulation, along with endometriosis model mice. The authors found that IL-33 and ST2 were higher in eESCs than in normal endometrial stromal cells, and that macrophages increased IL-33 output in the co-culture environment; IL-33/ST2 then improved eESC viability and migration and suppressed ferroptosis markers in erastin-treated cells by increasing SLC7A11 through downregulation of ATF3, mediated by the p38/JNK pathway. A key caveat is that the mechanistic and functional conclusions rely on in vitro eESC co-culture/stimulation systems and a mouse model, without detailed delineation of all downstream ferroptosis components (e.g., GPX4/GSH balance) in the provided text. This paper is centrally about endometriosis — it demonstrates macrophage-origin IL-33/ST2 inhibits eESC ferroptosis via the ATF3/SLC7A11 axis in endometriosis models.

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Abstract

Endometriosis is a gynecological inflammatory disease that is linked with immune cells, specifically macrophages. IL-33 secreted from macrophages is known to accelerate the progression of endometriosis. The periodic and repeated bleeding that occurs in women with endometriosis leads to excess iron in the microenvironment that is conducive to ferroptosis, a process related to intracellular ROS production, lipid peroxidation and mitochondrial damage. It is suggested that eESCs may specifically be able to inhibit ferroptosis. However, it is currently unclear whether IL-33 directly regulates ferroptosis to influence the disease course in endometriosis. In this study, eESCs co-cultured with macrophages or stimulated with IL-33/ST2 were observed to have increased cell viability and migration. Additionally, IL-33/ST2 decreased intracellular iron levels and lipid peroxidation in eESCs exposed to erastin treatment. Furthermore, IL-33/ST2 treatment resulted in a notable upregulation in SLC7A11 expression in eESCs due to the downregulation of negative transcription factor ATF3, thereby suppressing ferroptosis. The P38/JNK pathway activated by IL-33/ST2 was also found to inhibit the transcription factor ATF3. Therefore, we concluded that IL-33/ST2 inhibits the ATF3-mediated reduction in SLC7A11 transcript levels via the P38/JNK pathway. The findings reveal that macrophage-derived IL-33 upregulates SLC7A11 in eESCs through the p38/JNK/ATF3 pathway, ultimately resulting in protection against ferroptosis in eESCs. Moreover, we conducted an experiment using endometriosis model mice that showed that a combination of IL-33-Ab and erastin treatment alleviated the disease, showing the promise of combining immunotherapy and ferroptosis therapy.

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Condition tags

endometriosis

MeSH descriptors

Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Ferroptosis Ferroptosis Ferroptosis Ferroptosis Ferroptosis Ferroptosis Ferroptosis Activating Transcription Factor 3 Activating Transcription Factor 3 Activating Transcription Factor 3 Activating Transcription Factor 3 Activating Transcription Factor 3

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