Elevated Histone Lactylation Mediates Ferroptosis Resistance in Endometriosis Through the METTL3‐Regulated HIF1A/HMOX1 Signaling Pathway
Abstract Endometriosis (EMs) is a chronic gynecologic condition characterized by the growth of endometrial stromal and glandular tissue outside the uterine cavity of unknown etiology. Currently, ferroptosis resistance, increased glycolysis, and increased lactate production are identified in EMs. His...
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Wiley
2025-08-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202408220 |
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| author | Zongwen Liang Jinming Liu Yanling Gou Honglin Wang Zhi Li Yingying Cao Huiyan Zhang Ruru Bai Zongfeng Zhang |
| author_facet | Zongwen Liang Jinming Liu Yanling Gou Honglin Wang Zhi Li Yingying Cao Huiyan Zhang Ruru Bai Zongfeng Zhang |
| author_sort | Zongwen Liang |
| collection | DOAJ |
| description | Abstract Endometriosis (EMs) is a chronic gynecologic condition characterized by the growth of endometrial stromal and glandular tissue outside the uterine cavity of unknown etiology. Currently, ferroptosis resistance, increased glycolysis, and increased lactate production are identified in EMs. Histone lactylation is a lactate‐derived posttranslational modification that is recognized primarily for its role in epigenetic regulation. In this study, it is demonstrated that increased histone lactylation contributes to ferroptosis resistance in ectopic endometrial stromal cells (EESCs). Mechanistically, histone lactylation mediates ferroptosis resistance through the hypoxia‐inducible factor 1 alpha (HIF1A)/heme oxygenase 1 (HMOX1) signaling pathway, which is regulated by methyltransferase like 3 (METTL3). In vivo experiments reveal that combination therapy with 2‐deoxy‐D‐glucose (2‐DG) and erastin is more effective for the treatment of EMs. Together, the findings provide a theoretical basis for the pathogenesis of EMs and suggest that a combined treatment that inhibits histone lactylation and induces ferroptosis is an effective treatment for EMs. |
| format | Article |
| id | doaj-art-40c7a0197f1a4fddaac3146108169aa2 |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Wiley |
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| series | Advanced Science |
| spelling | doaj-art-40c7a0197f1a4fddaac3146108169aa22025-08-23T14:15:01ZengWileyAdvanced Science2198-38442025-08-011231n/an/a10.1002/advs.202408220Elevated Histone Lactylation Mediates Ferroptosis Resistance in Endometriosis Through the METTL3‐Regulated HIF1A/HMOX1 Signaling PathwayZongwen Liang0Jinming Liu1Yanling Gou2Honglin Wang3Zhi Li4Yingying Cao5Huiyan Zhang6Ruru Bai7Zongfeng Zhang8Department of Obstetrics and GynecologyThe Second Affiliated Hospital of Harbin Medical UniversityHarbin150086ChinaDepartment of Obstetrics and GynecologyThe Second Affiliated Hospital of Harbin Medical UniversityHarbin150086ChinaDepartment of Obstetrics and GynecologyThe Second Affiliated Hospital of Harbin Medical UniversityHarbin150086ChinaDepartment of Obstetrics and GynecologyThe Second Affiliated Hospital of Harbin Medical UniversityHarbin150086ChinaDepartment of Obstetrics and GynecologyThe Second Affiliated Hospital of Harbin Medical UniversityHarbin150086ChinaDepartment of Obstetrics and GynecologyThe Second Affiliated Hospital of Harbin Medical UniversityHarbin150086ChinaDepartment of Obstetrics and GynecologyThe Second Affiliated Hospital of Harbin Medical UniversityHarbin150086ChinaDepartment of Obstetrics and GynecologyThe Second Affiliated Hospital of Harbin Medical UniversityHarbin150086ChinaDepartment of Obstetrics and GynecologyThe Second Affiliated Hospital of Harbin Medical UniversityHarbin150086ChinaAbstract Endometriosis (EMs) is a chronic gynecologic condition characterized by the growth of endometrial stromal and glandular tissue outside the uterine cavity of unknown etiology. Currently, ferroptosis resistance, increased glycolysis, and increased lactate production are identified in EMs. Histone lactylation is a lactate‐derived posttranslational modification that is recognized primarily for its role in epigenetic regulation. In this study, it is demonstrated that increased histone lactylation contributes to ferroptosis resistance in ectopic endometrial stromal cells (EESCs). Mechanistically, histone lactylation mediates ferroptosis resistance through the hypoxia‐inducible factor 1 alpha (HIF1A)/heme oxygenase 1 (HMOX1) signaling pathway, which is regulated by methyltransferase like 3 (METTL3). In vivo experiments reveal that combination therapy with 2‐deoxy‐D‐glucose (2‐DG) and erastin is more effective for the treatment of EMs. Together, the findings provide a theoretical basis for the pathogenesis of EMs and suggest that a combined treatment that inhibits histone lactylation and induces ferroptosis is an effective treatment for EMs.https://doi.org/10.1002/advs.202408220endometriosisferroptosishif1ahistone lactylationhmox1mettl3 |
| spellingShingle | Zongwen Liang Jinming Liu Yanling Gou Honglin Wang Zhi Li Yingying Cao Huiyan Zhang Ruru Bai Zongfeng Zhang Elevated Histone Lactylation Mediates Ferroptosis Resistance in Endometriosis Through the METTL3‐Regulated HIF1A/HMOX1 Signaling Pathway Advanced Science endometriosis ferroptosis hif1a histone lactylation hmox1 mettl3 |
| title | Elevated Histone Lactylation Mediates Ferroptosis Resistance in Endometriosis Through the METTL3‐Regulated HIF1A/HMOX1 Signaling Pathway |
| title_full | Elevated Histone Lactylation Mediates Ferroptosis Resistance in Endometriosis Through the METTL3‐Regulated HIF1A/HMOX1 Signaling Pathway |
| title_fullStr | Elevated Histone Lactylation Mediates Ferroptosis Resistance in Endometriosis Through the METTL3‐Regulated HIF1A/HMOX1 Signaling Pathway |
| title_full_unstemmed | Elevated Histone Lactylation Mediates Ferroptosis Resistance in Endometriosis Through the METTL3‐Regulated HIF1A/HMOX1 Signaling Pathway |
| title_short | Elevated Histone Lactylation Mediates Ferroptosis Resistance in Endometriosis Through the METTL3‐Regulated HIF1A/HMOX1 Signaling Pathway |
| title_sort | elevated histone lactylation mediates ferroptosis resistance in endometriosis through the mettl3 regulated hif1a hmox1 signaling pathway |
| topic | endometriosis ferroptosis hif1a histone lactylation hmox1 mettl3 |
| url | https://doi.org/10.1002/advs.202408220 |
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