TRIM21‐Promoted FSP1 Plasma Membrane Translocation Confers Ferroptosis Resistance in Human Cancers
Abstract Ferroptosis, an iron‐dependent form of regulated cell death driven by excessive accumulation of lipid peroxides, has become a promising strategy in cancer treatment. Cancer cells exploit antioxidant proteins, including Ferroptosis Suppressor Protein 1 (FSP1), to prevent ferroptosis. In this...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-10-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202302318 |
| _version_ | 1826966251549753344 |
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| author | Jun Gong Yuhui Liu Wenjia Wang Ruizhi He Qilong Xia Lin Chen Chunle Zhao Yang Gao Yongkang Shi Yu Bai Yangwei Liao Qi Zhang Feng Zhu Min Wang Xu Li Renyi Qin |
| author_facet | Jun Gong Yuhui Liu Wenjia Wang Ruizhi He Qilong Xia Lin Chen Chunle Zhao Yang Gao Yongkang Shi Yu Bai Yangwei Liao Qi Zhang Feng Zhu Min Wang Xu Li Renyi Qin |
| author_sort | Jun Gong |
| collection | DOAJ |
| description | Abstract Ferroptosis, an iron‐dependent form of regulated cell death driven by excessive accumulation of lipid peroxides, has become a promising strategy in cancer treatment. Cancer cells exploit antioxidant proteins, including Ferroptosis Suppressor Protein 1 (FSP1), to prevent ferroptosis. In this study, it is found that the E3 ubiquitin ligase TRIM21 bound to FSP1 and mediated its ubiquitination on K322 and K366 residues via K63 linkage, which is essential for its membrane translocation and ferroptosis suppression ability. It is further verified the protective role of the TRIM21‐FSP1 axis in RSL3‐induced ferroptosis in cancer cells and a subcutaneous tumor model. Moreover, TRIM21 is highly expressed in multiple gastrointestinal (GI) tumors, and its expression is further stimulated upon ferroptosis induction in cancer cells and the KPC mouse model. In summary, This study identifies TRIM21 as a negative regulator of ferroptosis through K63 ubiquitination of FSP1, which can serve as a therapeutic target to enhance the chemosensitivity of tumors based on ferroptosis induction. |
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| id | doaj.art-135a3e2df28846809f66882744b2c577 |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2025-02-18T03:31:59Z |
| publishDate | 2023-10-01 |
| publisher | Wiley |
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| series | Advanced Science |
| spelling | doaj.art-135a3e2df28846809f66882744b2c5772024-11-22T13:11:48ZengWileyAdvanced Science2198-38442023-10-011029n/an/a10.1002/advs.202302318TRIM21‐Promoted FSP1 Plasma Membrane Translocation Confers Ferroptosis Resistance in Human CancersJun Gong0Yuhui Liu1Wenjia Wang2Ruizhi He3Qilong Xia4Lin Chen5Chunle Zhao6Yang Gao7Yongkang Shi8Yu Bai9Yangwei Liao10Qi Zhang11Feng Zhu12Min Wang13Xu Li14Renyi Qin15Department of Biliary‐Pancreatic Surgery Affiliated Tongji Hospital Tongji Medical College Huazhong University of Science and Technology 1095 Jiefang Ave Wuhan Hubei 430030 ChinaDepartment of Biliary‐Pancreatic Surgery Affiliated Tongji Hospital Tongji Medical College Huazhong University of Science and Technology 1095 Jiefang Ave Wuhan Hubei 430030 ChinaInstitute of Integrated Traditional Chinese and Western Medicine Affiliated Tongji Hospital Tongji Medical College Huazhong University of Science and Technology 1095 Jiefang Ave Wuhan Hubei 430030 ChinaDepartment of Biliary‐Pancreatic Surgery Affiliated Tongji Hospital Tongji Medical College Huazhong University of Science and Technology 1095 Jiefang Ave Wuhan Hubei 430030 ChinaDepartment of Biliary‐Pancreatic Surgery Affiliated Tongji Hospital Tongji Medical College Huazhong University of Science and Technology 1095 Jiefang Ave Wuhan Hubei 430030 ChinaDepartment of Biliary‐Pancreatic Surgery Affiliated Tongji Hospital Tongji Medical College Huazhong University of Science and Technology 1095 Jiefang Ave Wuhan Hubei 430030 ChinaDepartment of Biliary‐Pancreatic Surgery Affiliated Tongji Hospital Tongji Medical College Huazhong University of Science and Technology 1095 Jiefang Ave Wuhan Hubei 430030 ChinaDepartment of Biliary‐Pancreatic Surgery Affiliated Tongji Hospital Tongji Medical College Huazhong University of Science and Technology 1095 Jiefang Ave Wuhan Hubei 430030 ChinaDepartment of Biliary‐Pancreatic Surgery Affiliated Tongji Hospital Tongji Medical College Huazhong University of Science and Technology 1095 Jiefang Ave Wuhan Hubei 430030 ChinaDepartment of Biliary‐Pancreatic Surgery Affiliated Tongji Hospital Tongji Medical College Huazhong University of Science and Technology 1095 Jiefang Ave Wuhan Hubei 430030 ChinaDepartment of Biliary‐Pancreatic Surgery Affiliated Tongji Hospital Tongji Medical College Huazhong University of Science and Technology 1095 Jiefang Ave Wuhan Hubei 430030 ChinaDepartment of Plastic and Cosmetic Surgery Affiliated Tongji Hospital Tongji Medical College Huazhong University of Science and Technology 1095 Jiefang Ave Wuhan Hubei 430030 ChinaDepartment of Biliary‐Pancreatic Surgery Affiliated Tongji Hospital Tongji Medical College Huazhong University of Science and Technology 1095 Jiefang Ave Wuhan Hubei 430030 ChinaDepartment of Biliary‐Pancreatic Surgery Affiliated Tongji Hospital Tongji Medical College Huazhong University of Science and Technology 1095 Jiefang Ave Wuhan Hubei 430030 ChinaDepartment of Biliary‐Pancreatic Surgery Affiliated Tongji Hospital Tongji Medical College Huazhong University of Science and Technology 1095 Jiefang Ave Wuhan Hubei 430030 ChinaDepartment of Biliary‐Pancreatic Surgery Affiliated Tongji Hospital Tongji Medical College Huazhong University of Science and Technology 1095 Jiefang Ave Wuhan Hubei 430030 ChinaAbstract Ferroptosis, an iron‐dependent form of regulated cell death driven by excessive accumulation of lipid peroxides, has become a promising strategy in cancer treatment. Cancer cells exploit antioxidant proteins, including Ferroptosis Suppressor Protein 1 (FSP1), to prevent ferroptosis. In this study, it is found that the E3 ubiquitin ligase TRIM21 bound to FSP1 and mediated its ubiquitination on K322 and K366 residues via K63 linkage, which is essential for its membrane translocation and ferroptosis suppression ability. It is further verified the protective role of the TRIM21‐FSP1 axis in RSL3‐induced ferroptosis in cancer cells and a subcutaneous tumor model. Moreover, TRIM21 is highly expressed in multiple gastrointestinal (GI) tumors, and its expression is further stimulated upon ferroptosis induction in cancer cells and the KPC mouse model. In summary, This study identifies TRIM21 as a negative regulator of ferroptosis through K63 ubiquitination of FSP1, which can serve as a therapeutic target to enhance the chemosensitivity of tumors based on ferroptosis induction.https://doi.org/10.1002/advs.202302318cancerferroptosisFSP1TRIM21ubiquitination |
| spellingShingle | Jun Gong Yuhui Liu Wenjia Wang Ruizhi He Qilong Xia Lin Chen Chunle Zhao Yang Gao Yongkang Shi Yu Bai Yangwei Liao Qi Zhang Feng Zhu Min Wang Xu Li Renyi Qin TRIM21‐Promoted FSP1 Plasma Membrane Translocation Confers Ferroptosis Resistance in Human Cancers Advanced Science cancer ferroptosis FSP1 TRIM21 ubiquitination |
| title | TRIM21‐Promoted FSP1 Plasma Membrane Translocation Confers Ferroptosis Resistance in Human Cancers |
| title_full | TRIM21‐Promoted FSP1 Plasma Membrane Translocation Confers Ferroptosis Resistance in Human Cancers |
| title_fullStr | TRIM21‐Promoted FSP1 Plasma Membrane Translocation Confers Ferroptosis Resistance in Human Cancers |
| title_full_unstemmed | TRIM21‐Promoted FSP1 Plasma Membrane Translocation Confers Ferroptosis Resistance in Human Cancers |
| title_short | TRIM21‐Promoted FSP1 Plasma Membrane Translocation Confers Ferroptosis Resistance in Human Cancers |
| title_sort | trim21 promoted fsp1 plasma membrane translocation confers ferroptosis resistance in human cancers |
| topic | cancer ferroptosis FSP1 TRIM21 ubiquitination |
| url | https://doi.org/10.1002/advs.202302318 |
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