NANS suppresses NF-κB signaling to promote ferroptosis by perturbing iron homeostasis
Summary: Metastatic colorectal cancer (CRC) cells endure survival challenges, including treatment-induced ferroptosis. While adaptation to ferroptosis stress facilitates metastasis, reciprocal regulatory mechanisms remain unclear. Here, a CRISPR-Cas9 screen identifies N-acetylneuraminate synthase (N...
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| Language: | English |
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Elsevier
2025-05-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124725004723 |
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| author | Ziyang Wang Yuqin Di Lvlan Ye Wenzheng Fang Xiangqiong Wen Xiang Zhang Jiale Qin Youpeng Wang Kunhua Hu Zhenxin Zhu Weiling He Ying Chen |
| author_facet | Ziyang Wang Yuqin Di Lvlan Ye Wenzheng Fang Xiangqiong Wen Xiang Zhang Jiale Qin Youpeng Wang Kunhua Hu Zhenxin Zhu Weiling He Ying Chen |
| author_sort | Ziyang Wang |
| collection | DOAJ |
| description | Summary: Metastatic colorectal cancer (CRC) cells endure survival challenges, including treatment-induced ferroptosis. While adaptation to ferroptosis stress facilitates metastasis, reciprocal regulatory mechanisms remain unclear. Here, a CRISPR-Cas9 screen identifies N-acetylneuraminate synthase (NANS) as a ferroptosis promoter in CRC, regardless of its metabolic function. NANS expression is downregulated and correlates with poor prognosis in patients with CRC. Under ferroptotic stress, cyclin-dependent kinase 1 (CDK1) phosphorylates NANS at serine 275 (S275), triggering its dissociation from TAK1. Phosphorylated NANS is ubiquitinated by UBE2N at K246, leading to degradation, which activates TAK1-NF-κB signaling and upregulates the ferroptosis inhibitor FTH1, enabling metastasis via ferroptosis resistance. NANS pS275 levels are associated with tumor aggressiveness and clinical outcomes in patients with CRC. These findings indicate that NANS suppresses CRC metastasis by enhancing ferroptosis susceptibility, while CDK1-mediated phosphorylation at S275 drives adaptive resistance. Targeting this phosphorylation axis may improve ferroptosis-inducing therapies to restrict metastatic progression in CRC. |
| format | Article |
| id | doaj-art-466c73d4b29c4d3d9dbcaef986b918a6 |
| institution | OA Journals |
| issn | 2211-1247 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj-art-466c73d4b29c4d3d9dbcaef986b918a62025-08-20T02:15:06ZengElsevierCell Reports2211-12472025-05-0144511570110.1016/j.celrep.2025.115701NANS suppresses NF-κB signaling to promote ferroptosis by perturbing iron homeostasisZiyang Wang0Yuqin Di1Lvlan Ye2Wenzheng Fang3Xiangqiong Wen4Xiang Zhang5Jiale Qin6Youpeng Wang7Kunhua Hu8Zhenxin Zhu9Weiling He10Ying Chen11Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China; Corresponding authorMolecular Diagnosis and Gene Testing Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, ChinaOrgan Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, ChinaDepartment of Oncology, People’s Hospital Affiliated to Fujian University of Traditional Chinese Medicine, Fujian 350000, ChinaDepartment of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, ChinaDepartment of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, ChinaDepartment of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, ChinaCenter of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, ChinaGuangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, ChinaGastrointestinal Surgery Department, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, P.R. China; Corresponding authorDepartment of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China; Department of Gastrointestinal Surgery, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361000, China; Corresponding authorDepartment of Gastroenterology, Changhai Hospital affiliated to the Naval Medical University, Shanghai 200433, China; Corresponding authorSummary: Metastatic colorectal cancer (CRC) cells endure survival challenges, including treatment-induced ferroptosis. While adaptation to ferroptosis stress facilitates metastasis, reciprocal regulatory mechanisms remain unclear. Here, a CRISPR-Cas9 screen identifies N-acetylneuraminate synthase (NANS) as a ferroptosis promoter in CRC, regardless of its metabolic function. NANS expression is downregulated and correlates with poor prognosis in patients with CRC. Under ferroptotic stress, cyclin-dependent kinase 1 (CDK1) phosphorylates NANS at serine 275 (S275), triggering its dissociation from TAK1. Phosphorylated NANS is ubiquitinated by UBE2N at K246, leading to degradation, which activates TAK1-NF-κB signaling and upregulates the ferroptosis inhibitor FTH1, enabling metastasis via ferroptosis resistance. NANS pS275 levels are associated with tumor aggressiveness and clinical outcomes in patients with CRC. These findings indicate that NANS suppresses CRC metastasis by enhancing ferroptosis susceptibility, while CDK1-mediated phosphorylation at S275 drives adaptive resistance. Targeting this phosphorylation axis may improve ferroptosis-inducing therapies to restrict metastatic progression in CRC.http://www.sciencedirect.com/science/article/pii/S2211124725004723CP: Molecular biologyCP: Cancer |
| spellingShingle | Ziyang Wang Yuqin Di Lvlan Ye Wenzheng Fang Xiangqiong Wen Xiang Zhang Jiale Qin Youpeng Wang Kunhua Hu Zhenxin Zhu Weiling He Ying Chen NANS suppresses NF-κB signaling to promote ferroptosis by perturbing iron homeostasis Cell Reports CP: Molecular biology CP: Cancer |
| title | NANS suppresses NF-κB signaling to promote ferroptosis by perturbing iron homeostasis |
| title_full | NANS suppresses NF-κB signaling to promote ferroptosis by perturbing iron homeostasis |
| title_fullStr | NANS suppresses NF-κB signaling to promote ferroptosis by perturbing iron homeostasis |
| title_full_unstemmed | NANS suppresses NF-κB signaling to promote ferroptosis by perturbing iron homeostasis |
| title_short | NANS suppresses NF-κB signaling to promote ferroptosis by perturbing iron homeostasis |
| title_sort | nans suppresses nf κb signaling to promote ferroptosis by perturbing iron homeostasis |
| topic | CP: Molecular biology CP: Cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2211124725004723 |
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