Cholesterol confers resistance to Apatinib-mediated ferroptosis in gastric cancer
Abstract Background Gastric cancer is the fifth leading cause of cancer-related deaths worldwide. Apatinib is a third-line treatment for gastric cancer. However, the development of resistance significantly limits its efficacy, and effective and safe strategies to overcome Apatinib resistance remain...
Saved in:
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-07-01
|
| Series: | Cell & Bioscience |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13578-025-01435-5 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849389328347693056 |
|---|---|
| author | Zhiwei Li Chenxin Liu Minghao Wang Riqing Wei Ru Li Kaihua Huang Huayuan Liang Guoxin Li Liying Zhao |
| author_facet | Zhiwei Li Chenxin Liu Minghao Wang Riqing Wei Ru Li Kaihua Huang Huayuan Liang Guoxin Li Liying Zhao |
| author_sort | Zhiwei Li |
| collection | DOAJ |
| description | Abstract Background Gastric cancer is the fifth leading cause of cancer-related deaths worldwide. Apatinib is a third-line treatment for gastric cancer. However, the development of resistance significantly limits its efficacy, and effective and safe strategies to overcome Apatinib resistance remain elusive. Results We found that Apatinib-resistant gastric cancer cells (MGC803/AR and AGS/AR) exhibited increased cholesterol synthesis and elevated intracellular cholesterol levels, which contributed to Apatinib resistance. Further investigation identified 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) as one of the most upregulated genes in the cholesterol synthesis pathway. Inhibition of HMGCR not only suppressed the proliferation, migration, and invasion of resistant cells but also reduced their resistance to Apatinib. Moreover, Simvastatin, an HMGCR inhibitor, effectively resensitized resistant cells to Apatinib-induced ferroptosis, thereby enhancing the therapeutic efficacy of Apatinib both in vitro and in vivo. Conclusions These findings suggest that Simvastatin may serve as a novel and safe strategy to overcome Apatinib resistance in gastric cancer. |
| format | Article |
| id | doaj-art-602a6f12201a4bba9799e3db33159d5b |
| institution | Kabale University |
| issn | 2045-3701 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell & Bioscience |
| spelling | doaj-art-602a6f12201a4bba9799e3db33159d5b2025-08-20T03:42:00ZengBMCCell & Bioscience2045-37012025-07-0115111910.1186/s13578-025-01435-5Cholesterol confers resistance to Apatinib-mediated ferroptosis in gastric cancerZhiwei Li0Chenxin Liu1Minghao Wang2Riqing Wei3Ru Li4Kaihua Huang5Huayuan Liang6Guoxin Li7Liying Zhao8Department of General Surgery, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical UniversityDepartment of Clinical Laboratory, National Center for Respiratory Medicine, National Clinical Research Center for Respiratory Disease, State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical UniversityDepartment of General Surgery, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical UniversityDepartment of Biopharmaceutics, School of Laboratory Medicine and Biotechnology, Southern Medical UniversityDepartment of Biopharmaceutics, School of Laboratory Medicine and Biotechnology, Southern Medical UniversityDepartment of General Surgery, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical UniversityDepartment of Gastrointestinal Surgery, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua UniversityDepartment of General Surgery, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical UniversityDepartment of General Surgery, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical UniversityAbstract Background Gastric cancer is the fifth leading cause of cancer-related deaths worldwide. Apatinib is a third-line treatment for gastric cancer. However, the development of resistance significantly limits its efficacy, and effective and safe strategies to overcome Apatinib resistance remain elusive. Results We found that Apatinib-resistant gastric cancer cells (MGC803/AR and AGS/AR) exhibited increased cholesterol synthesis and elevated intracellular cholesterol levels, which contributed to Apatinib resistance. Further investigation identified 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) as one of the most upregulated genes in the cholesterol synthesis pathway. Inhibition of HMGCR not only suppressed the proliferation, migration, and invasion of resistant cells but also reduced their resistance to Apatinib. Moreover, Simvastatin, an HMGCR inhibitor, effectively resensitized resistant cells to Apatinib-induced ferroptosis, thereby enhancing the therapeutic efficacy of Apatinib both in vitro and in vivo. Conclusions These findings suggest that Simvastatin may serve as a novel and safe strategy to overcome Apatinib resistance in gastric cancer.https://doi.org/10.1186/s13578-025-01435-5Gastric cancerApatinibFerroptosisCholesterolHMGCR |
| spellingShingle | Zhiwei Li Chenxin Liu Minghao Wang Riqing Wei Ru Li Kaihua Huang Huayuan Liang Guoxin Li Liying Zhao Cholesterol confers resistance to Apatinib-mediated ferroptosis in gastric cancer Cell & Bioscience Gastric cancer Apatinib Ferroptosis Cholesterol HMGCR |
| title | Cholesterol confers resistance to Apatinib-mediated ferroptosis in gastric cancer |
| title_full | Cholesterol confers resistance to Apatinib-mediated ferroptosis in gastric cancer |
| title_fullStr | Cholesterol confers resistance to Apatinib-mediated ferroptosis in gastric cancer |
| title_full_unstemmed | Cholesterol confers resistance to Apatinib-mediated ferroptosis in gastric cancer |
| title_short | Cholesterol confers resistance to Apatinib-mediated ferroptosis in gastric cancer |
| title_sort | cholesterol confers resistance to apatinib mediated ferroptosis in gastric cancer |
| topic | Gastric cancer Apatinib Ferroptosis Cholesterol HMGCR |
| url | https://doi.org/10.1186/s13578-025-01435-5 |
| work_keys_str_mv | AT zhiweili cholesterolconfersresistancetoapatinibmediatedferroptosisingastriccancer AT chenxinliu cholesterolconfersresistancetoapatinibmediatedferroptosisingastriccancer AT minghaowang cholesterolconfersresistancetoapatinibmediatedferroptosisingastriccancer AT riqingwei cholesterolconfersresistancetoapatinibmediatedferroptosisingastriccancer AT ruli cholesterolconfersresistancetoapatinibmediatedferroptosisingastriccancer AT kaihuahuang cholesterolconfersresistancetoapatinibmediatedferroptosisingastriccancer AT huayuanliang cholesterolconfersresistancetoapatinibmediatedferroptosisingastriccancer AT guoxinli cholesterolconfersresistancetoapatinibmediatedferroptosisingastriccancer AT liyingzhao cholesterolconfersresistancetoapatinibmediatedferroptosisingastriccancer |