CROT overactivation within peroxisomes confers chemoresistance to non-small cell lung cancer by targeting fatty acid oxidation-Nrf2-ferroptosis resistance axis
A key factor that limits the therapeutic benefits for non-small cell lung cancer (NSCLC) patients is chemoresistance. Even so, a detailed understanding of the process involved in chemoresistance acquisition and development at molecular level in NSCLC is still lacking. Here, we established chemo-resi...
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Elsevier
2025-10-01
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| Series: | Pharmacological Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1043661825003366 |
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| author | Chunyu Hua Guohui Zhang Wendan Yu Jie Zhou Liyuan Ru Guoqing Xue Lina Zheng Meiyi Wang Yiwei Wang Dianlin Yu Qijing Wang Jiaxin Liu Ruonan Wang Wuguo Deng Ranran Tang Wei Guo |
| author_facet | Chunyu Hua Guohui Zhang Wendan Yu Jie Zhou Liyuan Ru Guoqing Xue Lina Zheng Meiyi Wang Yiwei Wang Dianlin Yu Qijing Wang Jiaxin Liu Ruonan Wang Wuguo Deng Ranran Tang Wei Guo |
| author_sort | Chunyu Hua |
| collection | DOAJ |
| description | A key factor that limits the therapeutic benefits for non-small cell lung cancer (NSCLC) patients is chemoresistance. Even so, a detailed understanding of the process involved in chemoresistance acquisition and development at molecular level in NSCLC is still lacking. Here, we established chemo-resistant NSCLC cells with obvious resistance to vincristine and paclitaxel and found the abnormal up-regulation of Carnitine O-Octanoyltransferase (CROT) in these cells by means of transcriptomics. In vitro and in vivo experiments demonstrate that the survival of NSCLC cells, especially chemosensitivity, including sensitivity to chemotherapeutics beyond vincristine and paclitaxel, was markedly influenced by CROT expression, and CROT silencing even reversed chemoresistance in NSCLC. Mechanistically, CROT is overactivated within peroxisomes in chemo-resistant NSCLC cells and drives chemoresistance relying on its involvement in lipid metabolism and oxidative stress processes. By mediating the production of Hydrogen Peroxide (H2O2) and reactive oxygen species (ROS), CROT stabilizes eryth-like-2 associated factor 2 (Nrf2) via preventing its ubiquitination and degradation, leading to more nuclear translocation of Nrf2, thereby inhibiting chemotherapy stress-induced ferroptosis. Accordingly, fatty acid oxidation inhibitors or ferroptosis activators rendered NSCLC cells increased sensitivity to chemotherapy in vitro and in vivo. Clinically and encouragingly, the aberrant up-regulation of CROT and Nrf2 was observed in chemo-resistant NSCLC tumor tissues and patients with higher CROT and/or Nrf2 level possessed a poor outcome. In sum, our study identifies CROT as a key promoter to drive chemoresistance of NSCLC cells by targeting fatty acid oxidation-Nrf2-ferroptosis resistance axis. The targeted inhibition of this axis and associated components individually or in cascades combined with chemotherapy may be exploited in avoiding or overcoming chemoresistance in NSCLC. |
| format | Article |
| id | doaj-art-8f25aa9730f94d55a2ff15ae8e0748b8 |
| institution | Kabale University |
| issn | 1096-1186 |
| language | English |
| publishDate | 2025-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Pharmacological Research |
| spelling | doaj-art-8f25aa9730f94d55a2ff15ae8e0748b82025-08-24T05:11:32ZengElsevierPharmacological Research1096-11862025-10-0122010791110.1016/j.phrs.2025.107911CROT overactivation within peroxisomes confers chemoresistance to non-small cell lung cancer by targeting fatty acid oxidation-Nrf2-ferroptosis resistance axisChunyu Hua0Guohui Zhang1Wendan Yu2Jie Zhou3Liyuan Ru4Guoqing Xue5Lina Zheng6Meiyi Wang7Yiwei Wang8Dianlin Yu9Qijing Wang10Jiaxin Liu11Ruonan Wang12Wuguo Deng13Ranran Tang14Wei Guo15Institute of Cancer Stem Cells & The Second Affiliated Hospital, Dalian Medical University, Dalian 116044, ChinaInstitute of Cancer Stem Cells & The Second Affiliated Hospital, Dalian Medical University, Dalian 116044, ChinaInstitute of Cancer Stem Cells & The Second Affiliated Hospital, Dalian Medical University, Dalian 116044, ChinaInstitute of Cancer Stem Cells & The Second Affiliated Hospital, Dalian Medical University, Dalian 116044, ChinaInstitute of Cancer Stem Cells & The Second Affiliated Hospital, Dalian Medical University, Dalian 116044, ChinaInstitute of Cancer Stem Cells & The Second Affiliated Hospital, Dalian Medical University, Dalian 116044, ChinaInstitute of Cancer Stem Cells & The Second Affiliated Hospital, Dalian Medical University, Dalian 116044, ChinaInstitute of Cancer Stem Cells & The Second Affiliated Hospital, Dalian Medical University, Dalian 116044, ChinaInstitute of Cancer Stem Cells & The Second Affiliated Hospital, Dalian Medical University, Dalian 116044, ChinaInstitute of Cancer Stem Cells & The Second Affiliated Hospital, Dalian Medical University, Dalian 116044, ChinaInstitute of Cancer Stem Cells & The Second Affiliated Hospital, Dalian Medical University, Dalian 116044, ChinaInstitute of Cancer Stem Cells & The Second Affiliated Hospital, Dalian Medical University, Dalian 116044, ChinaInstitute of Cancer Stem Cells & The Second Affiliated Hospital, Dalian Medical University, Dalian 116044, ChinaSun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China; Guangdong Provincial Hospital of Integrated Traditional Chinese and Western Medicine, Guangdong, China; Corresponding author at: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.Nanjing Women and Children's Healthcare Institute, Women's Hospital of Nanjing Medical University, Nanjing Women and Children's Healthcare Hospital, Nanjing 210004, China; Corresponding authors.Institute of Cancer Stem Cells & The Second Affiliated Hospital, Dalian Medical University, Dalian 116044, China; Corresponding authors.A key factor that limits the therapeutic benefits for non-small cell lung cancer (NSCLC) patients is chemoresistance. Even so, a detailed understanding of the process involved in chemoresistance acquisition and development at molecular level in NSCLC is still lacking. Here, we established chemo-resistant NSCLC cells with obvious resistance to vincristine and paclitaxel and found the abnormal up-regulation of Carnitine O-Octanoyltransferase (CROT) in these cells by means of transcriptomics. In vitro and in vivo experiments demonstrate that the survival of NSCLC cells, especially chemosensitivity, including sensitivity to chemotherapeutics beyond vincristine and paclitaxel, was markedly influenced by CROT expression, and CROT silencing even reversed chemoresistance in NSCLC. Mechanistically, CROT is overactivated within peroxisomes in chemo-resistant NSCLC cells and drives chemoresistance relying on its involvement in lipid metabolism and oxidative stress processes. By mediating the production of Hydrogen Peroxide (H2O2) and reactive oxygen species (ROS), CROT stabilizes eryth-like-2 associated factor 2 (Nrf2) via preventing its ubiquitination and degradation, leading to more nuclear translocation of Nrf2, thereby inhibiting chemotherapy stress-induced ferroptosis. Accordingly, fatty acid oxidation inhibitors or ferroptosis activators rendered NSCLC cells increased sensitivity to chemotherapy in vitro and in vivo. Clinically and encouragingly, the aberrant up-regulation of CROT and Nrf2 was observed in chemo-resistant NSCLC tumor tissues and patients with higher CROT and/or Nrf2 level possessed a poor outcome. In sum, our study identifies CROT as a key promoter to drive chemoresistance of NSCLC cells by targeting fatty acid oxidation-Nrf2-ferroptosis resistance axis. The targeted inhibition of this axis and associated components individually or in cascades combined with chemotherapy may be exploited in avoiding or overcoming chemoresistance in NSCLC.http://www.sciencedirect.com/science/article/pii/S1043661825003366NSCLCChemoresistanceCROTPeroxisomesNrf2Ferroptosis |
| spellingShingle | Chunyu Hua Guohui Zhang Wendan Yu Jie Zhou Liyuan Ru Guoqing Xue Lina Zheng Meiyi Wang Yiwei Wang Dianlin Yu Qijing Wang Jiaxin Liu Ruonan Wang Wuguo Deng Ranran Tang Wei Guo CROT overactivation within peroxisomes confers chemoresistance to non-small cell lung cancer by targeting fatty acid oxidation-Nrf2-ferroptosis resistance axis Pharmacological Research NSCLC Chemoresistance CROT Peroxisomes Nrf2 Ferroptosis |
| title | CROT overactivation within peroxisomes confers chemoresistance to non-small cell lung cancer by targeting fatty acid oxidation-Nrf2-ferroptosis resistance axis |
| title_full | CROT overactivation within peroxisomes confers chemoresistance to non-small cell lung cancer by targeting fatty acid oxidation-Nrf2-ferroptosis resistance axis |
| title_fullStr | CROT overactivation within peroxisomes confers chemoresistance to non-small cell lung cancer by targeting fatty acid oxidation-Nrf2-ferroptosis resistance axis |
| title_full_unstemmed | CROT overactivation within peroxisomes confers chemoresistance to non-small cell lung cancer by targeting fatty acid oxidation-Nrf2-ferroptosis resistance axis |
| title_short | CROT overactivation within peroxisomes confers chemoresistance to non-small cell lung cancer by targeting fatty acid oxidation-Nrf2-ferroptosis resistance axis |
| title_sort | crot overactivation within peroxisomes confers chemoresistance to non small cell lung cancer by targeting fatty acid oxidation nrf2 ferroptosis resistance axis |
| topic | NSCLC Chemoresistance CROT Peroxisomes Nrf2 Ferroptosis |
| url | http://www.sciencedirect.com/science/article/pii/S1043661825003366 |
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