Dysregulated lipids homeostasis disrupts CHAC1-mediated ferroptosis driving fibroblast growth factor receptor tyrosine kinase inhibitor AZD4547 resistance in gastric cancer
Aims: This study investigates the mechanisms underlying acquired resistance to FGFR tyrosine kinase inhibitor (FGFR-TKI) in gastric cancer (GC), focusing on the interplay between ferroptosis and lipid metabolism of tumor cells. Methods: We constructed FGFR-TKI-resistant cell lines from GC cells. RNA...
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Elsevier
2025-07-01
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| Series: | Redox Biology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S221323172500206X |
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| author | Jingwen Chen Yedi Huang Daocheng Zuo Ruimin Shan Songmao Li Ran Li Dong Hua Qiang Zhan Xudong Song Yun Chen Pei Ma Ling Ma Guoquan Tao Yongqian Shu |
| author_facet | Jingwen Chen Yedi Huang Daocheng Zuo Ruimin Shan Songmao Li Ran Li Dong Hua Qiang Zhan Xudong Song Yun Chen Pei Ma Ling Ma Guoquan Tao Yongqian Shu |
| author_sort | Jingwen Chen |
| collection | DOAJ |
| description | Aims: This study investigates the mechanisms underlying acquired resistance to FGFR tyrosine kinase inhibitor (FGFR-TKI) in gastric cancer (GC), focusing on the interplay between ferroptosis and lipid metabolism of tumor cells. Methods: We constructed FGFR-TKI-resistant cell lines from GC cells. RNA sequencing was performed to identify differentially expressed genes (DEGs) related to ferroptosis and assess lipid metabolism in resistant cells. GC microenvironment lipid profile was characterized by HPLC-MS/MS lipidomics. The effects of CHAC1 and cholesterol synthesis modulation on ferroptosis and FGFR-TKI resistance were assessed using in vitro and in vivo models. Results: We found that FGFR-TKI can induce ferroptosis in FGFR-TKI-sensitive cells, while resistant cells exhibit decreased sensitivity to ferroptosis due to reduced CHAC1 expression, a key glutathione-specific degrading enzyme. Overexpression of CHAC1 enhances FGFR-TKI cytotoxicity. Additionally, cholesterol accumulation in resistant cells, associated with diminished stearic acid (SA) uptake, confers FGFR-TKI-induced ferroptosis resistance. In vivo studies show that CHAC1 overexpression or cholesterol synthesis inhibition can reverse FGFR-TKI resistance, which is dependent on ferroptosis. Conclusions: Dysregulated lipid homeostasis downregulated CHAC1-mediated ferroptosis, leading to FGFR-TKI resistance in gastric cancer. Overexpression of CHAC1 or inhibiting cholesterol synthesis presents promising therapeutic strategies to overcome FGFR-TKI resistance in GC. |
| format | Article |
| id | doaj-art-3a3c586fe2ec4b7bbf78aac5514e2e81 |
| institution | OA Journals |
| issn | 2213-2317 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj-art-3a3c586fe2ec4b7bbf78aac5514e2e812025-08-20T02:02:00ZengElsevierRedox Biology2213-23172025-07-018410369310.1016/j.redox.2025.103693Dysregulated lipids homeostasis disrupts CHAC1-mediated ferroptosis driving fibroblast growth factor receptor tyrosine kinase inhibitor AZD4547 resistance in gastric cancerJingwen Chen0Yedi Huang1Daocheng Zuo2Ruimin Shan3Songmao Li4Ran Li5Dong Hua6Qiang Zhan7Xudong Song8Yun Chen9Pei Ma10Ling Ma11Guoquan Tao12Yongqian Shu13Department of Oncology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 210029, PR China; Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211166, PR ChinaDepartment of Immunology, School of Basic Medical Sciences, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Nanjing Medical University, Nanjing, 210000, PR China; Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211166, PR ChinaDepartment of Immunology, School of Basic Medical Sciences, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Nanjing Medical University, Nanjing, 210000, PR ChinaDepartment of Immunology, School of Basic Medical Sciences, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Nanjing Medical University, Nanjing, 210000, PR ChinaDepartment of Immunology, School of Basic Medical Sciences, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Nanjing Medical University, Nanjing, 210000, PR ChinaDepartment of Immunology, School of Basic Medical Sciences, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Nanjing Medical University, Nanjing, 210000, PR ChinaThe Affiliated Wuxi People's Hospital of Nanjing Medical University, School of Medicine, Jiangnan University, Wuxi, 214000, PR ChinaDepartments of Gastroenterology, the Affiliated Wuxi People's Hospital of Nanjing Medical University & Department of Medical Genetics, Nanjing Medical University, Nanjing, 210000, PR ChinaDepartment of Gastrointestinal surgery, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huaian, 223300, PR ChinaDepartment of Immunology, School of Basic Medical Sciences, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Nanjing Medical University, Nanjing, 210000, PR China; Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211166, PR China; Corresponding author. Department of Immunology, School of Basic Medical Sciences, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Nanjing Medical University, Nanjing, 210000, PR China.Department of Oncology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 210029, PR China; Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211166, PR China; Corresponding author. Department of Oncology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 210029, PR China.Department of Oncology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 210029, PR China; Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211166, PR China; Corresponding author. Department of Oncology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 210029, PR China.Gusu School, Nanjing Medical University, Suzhou, 211166, PR China; Corresponding author.Department of Oncology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 210029, PR China; Gusu School, Nanjing Medical University, Suzhou, 211166, PR China; Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211166, PR China; Corresponding Author. Department of Oncology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 210029, PR China.Aims: This study investigates the mechanisms underlying acquired resistance to FGFR tyrosine kinase inhibitor (FGFR-TKI) in gastric cancer (GC), focusing on the interplay between ferroptosis and lipid metabolism of tumor cells. Methods: We constructed FGFR-TKI-resistant cell lines from GC cells. RNA sequencing was performed to identify differentially expressed genes (DEGs) related to ferroptosis and assess lipid metabolism in resistant cells. GC microenvironment lipid profile was characterized by HPLC-MS/MS lipidomics. The effects of CHAC1 and cholesterol synthesis modulation on ferroptosis and FGFR-TKI resistance were assessed using in vitro and in vivo models. Results: We found that FGFR-TKI can induce ferroptosis in FGFR-TKI-sensitive cells, while resistant cells exhibit decreased sensitivity to ferroptosis due to reduced CHAC1 expression, a key glutathione-specific degrading enzyme. Overexpression of CHAC1 enhances FGFR-TKI cytotoxicity. Additionally, cholesterol accumulation in resistant cells, associated with diminished stearic acid (SA) uptake, confers FGFR-TKI-induced ferroptosis resistance. In vivo studies show that CHAC1 overexpression or cholesterol synthesis inhibition can reverse FGFR-TKI resistance, which is dependent on ferroptosis. Conclusions: Dysregulated lipid homeostasis downregulated CHAC1-mediated ferroptosis, leading to FGFR-TKI resistance in gastric cancer. Overexpression of CHAC1 or inhibiting cholesterol synthesis presents promising therapeutic strategies to overcome FGFR-TKI resistance in GC.http://www.sciencedirect.com/science/article/pii/S221323172500206XGastric cancerFGFR-TKI resistanceFerroptosisCHAC1Cholesterol metabolismLipidomics |
| spellingShingle | Jingwen Chen Yedi Huang Daocheng Zuo Ruimin Shan Songmao Li Ran Li Dong Hua Qiang Zhan Xudong Song Yun Chen Pei Ma Ling Ma Guoquan Tao Yongqian Shu Dysregulated lipids homeostasis disrupts CHAC1-mediated ferroptosis driving fibroblast growth factor receptor tyrosine kinase inhibitor AZD4547 resistance in gastric cancer Redox Biology Gastric cancer FGFR-TKI resistance Ferroptosis CHAC1 Cholesterol metabolism Lipidomics |
| title | Dysregulated lipids homeostasis disrupts CHAC1-mediated ferroptosis driving fibroblast growth factor receptor tyrosine kinase inhibitor AZD4547 resistance in gastric cancer |
| title_full | Dysregulated lipids homeostasis disrupts CHAC1-mediated ferroptosis driving fibroblast growth factor receptor tyrosine kinase inhibitor AZD4547 resistance in gastric cancer |
| title_fullStr | Dysregulated lipids homeostasis disrupts CHAC1-mediated ferroptosis driving fibroblast growth factor receptor tyrosine kinase inhibitor AZD4547 resistance in gastric cancer |
| title_full_unstemmed | Dysregulated lipids homeostasis disrupts CHAC1-mediated ferroptosis driving fibroblast growth factor receptor tyrosine kinase inhibitor AZD4547 resistance in gastric cancer |
| title_short | Dysregulated lipids homeostasis disrupts CHAC1-mediated ferroptosis driving fibroblast growth factor receptor tyrosine kinase inhibitor AZD4547 resistance in gastric cancer |
| title_sort | dysregulated lipids homeostasis disrupts chac1 mediated ferroptosis driving fibroblast growth factor receptor tyrosine kinase inhibitor azd4547 resistance in gastric cancer |
| topic | Gastric cancer FGFR-TKI resistance Ferroptosis CHAC1 Cholesterol metabolism Lipidomics |
| url | http://www.sciencedirect.com/science/article/pii/S221323172500206X |
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