TRIM21 Promotes Tumor Growth and Gemcitabine Resistance in Pancreatic Cancer by Inhibiting EPHX1‐Mediated Arachidonic Acid Metabolism
Abstract Pancreatic cancer (PC) progresses rapidly, and gemcitabine‐based chemotherapy has brought only limited efficacy. Identifying key drivers and therapeutic targets holds significant clinical value. In this study, through comprehensive analysis of multiple PC databases, this work identifies TRI...
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Wiley
2025-02-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202413674 |
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| author | Xiaona Fan Yisheng Dai Chuanfeng Mo Hengzhen Li Xindi Luan Bojun Wang Jiani Yang Guangtao Jiao XiaoLin Lu Zhuo Chen Yuanyu Liao Ling Qu Huike Yang Changjie Lou Chao Liu Zhiwei Li |
| author_facet | Xiaona Fan Yisheng Dai Chuanfeng Mo Hengzhen Li Xindi Luan Bojun Wang Jiani Yang Guangtao Jiao XiaoLin Lu Zhuo Chen Yuanyu Liao Ling Qu Huike Yang Changjie Lou Chao Liu Zhiwei Li |
| author_sort | Xiaona Fan |
| collection | DOAJ |
| description | Abstract Pancreatic cancer (PC) progresses rapidly, and gemcitabine‐based chemotherapy has brought only limited efficacy. Identifying key drivers and therapeutic targets holds significant clinical value. In this study, through comprehensive analysis of multiple PC databases, this work identifies TRIM21 as a promising driver mediator. This work further performs loss‐ and gain‐of‐function assays for TRIM21, revealing that TRIM21 knockout inhibits tumor proliferation and gemcitabine resistance both in vitro and vivo. Lipidomics reveal that silencing TRIM21 reduce the arachidonic acid production, and inhibit ferroptosis. Mechanically, through proteomics, ubiquitomics, and liquid chromatography‐tandem mass spectrometry analysis, the key metabolic enzyme of arachidonic acid ‐EPHX1 is identified as a downstream substrate of TRIM21. TRIM21 interacts with EPHX1 through its SPRY domain and promotes ubiquitin‐mediated degradation of EPHX1 via K33‐ and K48‐linked ubiquitination at the K105 site. Given the targeting potential, this work screens Bezafibrate to block the interaction between TRIM21 and EPHX1 and validates its sensitizing effect. In summary, TRIM21 promotes tumour growth and gemcitabine resistance in PC by inhibiting EPHX1‐mediated arachidonic acid metabolism. This provides a novel and promising target for clinical treatment of PC. |
| format | Article |
| id | doaj-art-3b1d1561250345a6b8cad11b7fbc2fbc |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-3b1d1561250345a6b8cad11b7fbc2fbc2025-08-20T03:49:36ZengWileyAdvanced Science2198-38442025-02-01128n/an/a10.1002/advs.202413674TRIM21 Promotes Tumor Growth and Gemcitabine Resistance in Pancreatic Cancer by Inhibiting EPHX1‐Mediated Arachidonic Acid MetabolismXiaona Fan0Yisheng Dai1Chuanfeng Mo2Hengzhen Li3Xindi Luan4Bojun Wang5Jiani Yang6Guangtao Jiao7XiaoLin Lu8Zhuo Chen9Yuanyu Liao10Ling Qu11Huike Yang12Changjie Lou13Chao Liu14Zhiwei Li15Department of Gastrointestinal Medical Oncology Harbin Medical University Cancer Hospital Harbin 150081 P. R. ChinaDepartment of Gastrointestinal Medical Oncology Harbin Medical University Cancer Hospital Harbin 150081 P. R. ChinaDepartment of Gastrointestinal Medical Oncology Harbin Medical University Cancer Hospital Harbin 150081 P. R. ChinaDepartment of Gastrointestinal Medical Oncology Harbin Medical University Cancer Hospital Harbin 150081 P. R. ChinaDepartment of Gastrointestinal Medical Oncology Harbin Medical University Cancer Hospital Harbin 150081 P. R. ChinaDepartment of Gastrointestinal Medical Oncology Harbin Medical University Cancer Hospital Harbin 150081 P. R. ChinaDepartment of Gastrointestinal Medical Oncology Harbin Medical University Cancer Hospital Harbin 150081 P. R. ChinaDepartment of Gastrointestinal Medical Oncology Harbin Medical University Cancer Hospital Harbin 150081 P. R. ChinaDepartment of Orthopedic Surgery Harbin Medical University Cancer Hospital Harbin 150081 ChinaDepartment of Gastrointestinal Medical Oncology Harbin Medical University Cancer Hospital Harbin 150081 P. R. ChinaDepartment of Gastrointestinal Medical Oncology Harbin Medical University Cancer Hospital Harbin 150081 P. R. ChinaDepartment of Gastrointestinal Medical Oncology Harbin Medical University Cancer Hospital Harbin 150081 P. R. ChinaDepartment of Gastrointestinal Medical Oncology Harbin Medical University Cancer Hospital Harbin 150081 P. R. ChinaDepartment of Gastrointestinal Medical Oncology Harbin Medical University Cancer Hospital Harbin 150081 P. R. ChinaDepartment of Gastrointestinal Medical Oncology Harbin Medical University Cancer Hospital Harbin 150081 P. R. ChinaDepartment of Gastrointestinal Medical Oncology Harbin Medical University Cancer Hospital Harbin 150081 P. R. ChinaAbstract Pancreatic cancer (PC) progresses rapidly, and gemcitabine‐based chemotherapy has brought only limited efficacy. Identifying key drivers and therapeutic targets holds significant clinical value. In this study, through comprehensive analysis of multiple PC databases, this work identifies TRIM21 as a promising driver mediator. This work further performs loss‐ and gain‐of‐function assays for TRIM21, revealing that TRIM21 knockout inhibits tumor proliferation and gemcitabine resistance both in vitro and vivo. Lipidomics reveal that silencing TRIM21 reduce the arachidonic acid production, and inhibit ferroptosis. Mechanically, through proteomics, ubiquitomics, and liquid chromatography‐tandem mass spectrometry analysis, the key metabolic enzyme of arachidonic acid ‐EPHX1 is identified as a downstream substrate of TRIM21. TRIM21 interacts with EPHX1 through its SPRY domain and promotes ubiquitin‐mediated degradation of EPHX1 via K33‐ and K48‐linked ubiquitination at the K105 site. Given the targeting potential, this work screens Bezafibrate to block the interaction between TRIM21 and EPHX1 and validates its sensitizing effect. In summary, TRIM21 promotes tumour growth and gemcitabine resistance in PC by inhibiting EPHX1‐mediated arachidonic acid metabolism. This provides a novel and promising target for clinical treatment of PC.https://doi.org/10.1002/advs.202413674arachidonic acid metabolismEPHX1pancreatic cancerTRIM21ubiquitination |
| spellingShingle | Xiaona Fan Yisheng Dai Chuanfeng Mo Hengzhen Li Xindi Luan Bojun Wang Jiani Yang Guangtao Jiao XiaoLin Lu Zhuo Chen Yuanyu Liao Ling Qu Huike Yang Changjie Lou Chao Liu Zhiwei Li TRIM21 Promotes Tumor Growth and Gemcitabine Resistance in Pancreatic Cancer by Inhibiting EPHX1‐Mediated Arachidonic Acid Metabolism Advanced Science arachidonic acid metabolism EPHX1 pancreatic cancer TRIM21 ubiquitination |
| title | TRIM21 Promotes Tumor Growth and Gemcitabine Resistance in Pancreatic Cancer by Inhibiting EPHX1‐Mediated Arachidonic Acid Metabolism |
| title_full | TRIM21 Promotes Tumor Growth and Gemcitabine Resistance in Pancreatic Cancer by Inhibiting EPHX1‐Mediated Arachidonic Acid Metabolism |
| title_fullStr | TRIM21 Promotes Tumor Growth and Gemcitabine Resistance in Pancreatic Cancer by Inhibiting EPHX1‐Mediated Arachidonic Acid Metabolism |
| title_full_unstemmed | TRIM21 Promotes Tumor Growth and Gemcitabine Resistance in Pancreatic Cancer by Inhibiting EPHX1‐Mediated Arachidonic Acid Metabolism |
| title_short | TRIM21 Promotes Tumor Growth and Gemcitabine Resistance in Pancreatic Cancer by Inhibiting EPHX1‐Mediated Arachidonic Acid Metabolism |
| title_sort | trim21 promotes tumor growth and gemcitabine resistance in pancreatic cancer by inhibiting ephx1 mediated arachidonic acid metabolism |
| topic | arachidonic acid metabolism EPHX1 pancreatic cancer TRIM21 ubiquitination |
| url | https://doi.org/10.1002/advs.202413674 |
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