CLDN6 triggers NRF2-mediated ferroptosis through recruiting DLG1/PBK complex in breast cancer
Abstract We previously identified CLDN6 as a pivotal tumor suppressor in breast cancer and unexpectedly discovered that overexpression of CLDN6 resulted in characteristic ultrastructural alterations of ferroptosis. However, the exact mechanism by which CLDN6 triggers ferroptosis is still elusive in...
Saved in:
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2025-02-01
|
| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07448-9 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849225813109506048 |
|---|---|
| author | Da Qi Yan Lu Huinan Qu Yuan Dong Qiu Jin Minghao Sun Chengshi Quan |
| author_facet | Da Qi Yan Lu Huinan Qu Yuan Dong Qiu Jin Minghao Sun Chengshi Quan |
| author_sort | Da Qi |
| collection | DOAJ |
| description | Abstract We previously identified CLDN6 as a pivotal tumor suppressor in breast cancer and unexpectedly discovered that overexpression of CLDN6 resulted in characteristic ultrastructural alterations of ferroptosis. However, the exact mechanism by which CLDN6 triggers ferroptosis is still elusive in breast cancer. Our study showed that CLDN6 was associated with ferroptosis in breast cancer patients. The integration of CLDN6 and ferroptosis demonstrated remarkable predictive prognostic performance. We observed that CLDN6 triggers NRF2-mediated ferroptosis in vitro and in vivo. Mechanistically, CLDN6 enhanced nuclear export of NRF2 by regulating the PBK-dependent AKT/GSK3β/FYN axis. Further CLDN6 recruited PBK to the cell membrane through the endosomal pathway and bound with the DLG1/PBK complex, thereby promoted the degradation of PBK by the UPS. This study elucidates the previously unrecognized mechanism of CLDN6 triggering NRF2-mediated ferroptosis through recruiting DLG1/PBK complex. This study provides a reliable biomarker for predicting prognosis and is anticipated to guide the selection of therapies targeting ferroptosis in breast cancer. |
| format | Article |
| id | doaj-art-063b4f176e7e4f1e952d1ab4cf19b58d |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-063b4f176e7e4f1e952d1ab4cf19b58d2025-08-24T11:54:21ZengNature Publishing GroupCell Death and Disease2041-48892025-02-0116111110.1038/s41419-025-07448-9CLDN6 triggers NRF2-mediated ferroptosis through recruiting DLG1/PBK complex in breast cancerDa Qi0Yan Lu1Huinan Qu2Yuan Dong3Qiu Jin4Minghao Sun5Chengshi Quan6The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin UniversityDepartment of Anatomy, College of Basic Medical Sciences, Jilin UniversityDepartment of Histology and Embryology, College of Basic Medical Sciences, Jilin UniversityThe Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin UniversityThe Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin UniversityThe Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin UniversityThe Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin UniversityAbstract We previously identified CLDN6 as a pivotal tumor suppressor in breast cancer and unexpectedly discovered that overexpression of CLDN6 resulted in characteristic ultrastructural alterations of ferroptosis. However, the exact mechanism by which CLDN6 triggers ferroptosis is still elusive in breast cancer. Our study showed that CLDN6 was associated with ferroptosis in breast cancer patients. The integration of CLDN6 and ferroptosis demonstrated remarkable predictive prognostic performance. We observed that CLDN6 triggers NRF2-mediated ferroptosis in vitro and in vivo. Mechanistically, CLDN6 enhanced nuclear export of NRF2 by regulating the PBK-dependent AKT/GSK3β/FYN axis. Further CLDN6 recruited PBK to the cell membrane through the endosomal pathway and bound with the DLG1/PBK complex, thereby promoted the degradation of PBK by the UPS. This study elucidates the previously unrecognized mechanism of CLDN6 triggering NRF2-mediated ferroptosis through recruiting DLG1/PBK complex. This study provides a reliable biomarker for predicting prognosis and is anticipated to guide the selection of therapies targeting ferroptosis in breast cancer.https://doi.org/10.1038/s41419-025-07448-9 |
| spellingShingle | Da Qi Yan Lu Huinan Qu Yuan Dong Qiu Jin Minghao Sun Chengshi Quan CLDN6 triggers NRF2-mediated ferroptosis through recruiting DLG1/PBK complex in breast cancer Cell Death and Disease |
| title | CLDN6 triggers NRF2-mediated ferroptosis through recruiting DLG1/PBK complex in breast cancer |
| title_full | CLDN6 triggers NRF2-mediated ferroptosis through recruiting DLG1/PBK complex in breast cancer |
| title_fullStr | CLDN6 triggers NRF2-mediated ferroptosis through recruiting DLG1/PBK complex in breast cancer |
| title_full_unstemmed | CLDN6 triggers NRF2-mediated ferroptosis through recruiting DLG1/PBK complex in breast cancer |
| title_short | CLDN6 triggers NRF2-mediated ferroptosis through recruiting DLG1/PBK complex in breast cancer |
| title_sort | cldn6 triggers nrf2 mediated ferroptosis through recruiting dlg1 pbk complex in breast cancer |
| url | https://doi.org/10.1038/s41419-025-07448-9 |
| work_keys_str_mv | AT daqi cldn6triggersnrf2mediatedferroptosisthroughrecruitingdlg1pbkcomplexinbreastcancer AT yanlu cldn6triggersnrf2mediatedferroptosisthroughrecruitingdlg1pbkcomplexinbreastcancer AT huinanqu cldn6triggersnrf2mediatedferroptosisthroughrecruitingdlg1pbkcomplexinbreastcancer AT yuandong cldn6triggersnrf2mediatedferroptosisthroughrecruitingdlg1pbkcomplexinbreastcancer AT qiujin cldn6triggersnrf2mediatedferroptosisthroughrecruitingdlg1pbkcomplexinbreastcancer AT minghaosun cldn6triggersnrf2mediatedferroptosisthroughrecruitingdlg1pbkcomplexinbreastcancer AT chengshiquan cldn6triggersnrf2mediatedferroptosisthroughrecruitingdlg1pbkcomplexinbreastcancer |