Inhibition of glutathione peroxidase 4 suppresses gastric cancer peritoneal metastasis via regulation of RCC2 homeostasis
Gastric cancer (GC) is one of the most lethal malignancies due to high metastatic rate, making the identification of new therapeutic targets critical for developing effective anti-GC treatments. Glutathione peroxidase 4 (GPx4), a key regulator of ferroptosis and redox homeostasis, contributes to pro...
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Elsevier
2025-03-01
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| Series: | Redox Biology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231725000321 |
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| author | Can Hu Jingli Xu Yanqiang Zhang Ruolan Zhang Siwei Pan Jiahui Chen Yan Wang Qianyu Zhao Yuqi Wang Weiwei Zhu Mengxuan Cao Shengjie Zhang Dan Zu Zhiyuan Xu Ji Jing Xiangdong Cheng |
| author_facet | Can Hu Jingli Xu Yanqiang Zhang Ruolan Zhang Siwei Pan Jiahui Chen Yan Wang Qianyu Zhao Yuqi Wang Weiwei Zhu Mengxuan Cao Shengjie Zhang Dan Zu Zhiyuan Xu Ji Jing Xiangdong Cheng |
| author_sort | Can Hu |
| collection | DOAJ |
| description | Gastric cancer (GC) is one of the most lethal malignancies due to high metastatic rate, making the identification of new therapeutic targets critical for developing effective anti-GC treatments. Glutathione peroxidase 4 (GPx4), a key regulator of ferroptosis and redox homeostasis, contributes to progression and influences patient survival. However, the molecular mechanism by which GPx4 drives GC progression has not been fully illuminated. In this study, we found that GPx4 was overexpressed and negatively associated with poor prognosis and distant metastasis, as confirmed by single-cell RNA sequencing (scRNA-seq) and validation with retrospective clinical samples. GPx4 knockdown suppressed GC invasion, migration and peritoneal metastasis in vitro and in vivo. Proteomic analysis revealed that GPx4 expression regulated the Homeostasis of RCC2, an oncogene link to epithelial-mesenchymal transition (EMT). Furthermore, we demonstrated that the reactive oxygen species (ROS) accumulation induced by GPx4 inhibition or knockdown activated aurora A phosphorylation, leading to RCC2 ubiquitination and degradation, thereby suppressing peritoneal metastasis in GC. We also identified that the Thr418 phosphorylation site is crucial for RCC2 ubiquitination at the K377, initiating its degradation in response to ROS. In conclusion, our results indicate that GPx4 acts as an oncogene in GC, and that suppressing GPx4 prevents GC progression and metastasis by promoting ROS-induced RCC2 ubiquitination and degradation. |
| format | Article |
| id | doaj-art-24ef8b4985d344d4825e6392007333cc |
| institution | Kabale University |
| issn | 2213-2317 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj-art-24ef8b4985d344d4825e6392007333cc2025-02-06T05:11:35ZengElsevierRedox Biology2213-23172025-03-0180103519Inhibition of glutathione peroxidase 4 suppresses gastric cancer peritoneal metastasis via regulation of RCC2 homeostasisCan Hu0Jingli Xu1Yanqiang Zhang2Ruolan Zhang3Siwei Pan4Jiahui Chen5Yan Wang6Qianyu Zhao7Yuqi Wang8Weiwei Zhu9Mengxuan Cao10Shengjie Zhang11Dan Zu12Zhiyuan Xu13Ji Jing14Xiangdong Cheng15Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China; Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, 310022, China; Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, 310022, ChinaDepartment of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China; Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, 310022, China; Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, 310022, ChinaDepartment of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China; Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, 310022, China; Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, 310022, ChinaDepartment of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China; Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, 310022, China; Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, 310022, ChinaDepartment of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China; Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, 310022, China; Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, 310022, ChinaDepartment of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China; Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, 310022, China; Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, 310022, ChinaZhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, 310022, China; Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, 310022, China; Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, ChinaDepartment of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China; Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, 310022, China; Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, 310022, ChinaDepartment of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China; Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, 310022, China; Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, 310022, ChinaDepartment of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China; Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, 310022, China; Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, 310022, ChinaDepartment of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China; Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, 310022, China; Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, 310022, ChinaZhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, 310022, China; Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, 310022, ChinaZhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, 310022, China; Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, 310022, ChinaDepartment of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China; Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, 310022, China; Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, 310022, China; Corresponding author. Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China.Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, 310022, China; Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, 310022, China; Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China; Corresponding author. Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China.Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China; Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, 310022, China; Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, 310022, China; Corresponding author. Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China.chengxd@zjcc.org.cnGastric cancer (GC) is one of the most lethal malignancies due to high metastatic rate, making the identification of new therapeutic targets critical for developing effective anti-GC treatments. Glutathione peroxidase 4 (GPx4), a key regulator of ferroptosis and redox homeostasis, contributes to progression and influences patient survival. However, the molecular mechanism by which GPx4 drives GC progression has not been fully illuminated. In this study, we found that GPx4 was overexpressed and negatively associated with poor prognosis and distant metastasis, as confirmed by single-cell RNA sequencing (scRNA-seq) and validation with retrospective clinical samples. GPx4 knockdown suppressed GC invasion, migration and peritoneal metastasis in vitro and in vivo. Proteomic analysis revealed that GPx4 expression regulated the Homeostasis of RCC2, an oncogene link to epithelial-mesenchymal transition (EMT). Furthermore, we demonstrated that the reactive oxygen species (ROS) accumulation induced by GPx4 inhibition or knockdown activated aurora A phosphorylation, leading to RCC2 ubiquitination and degradation, thereby suppressing peritoneal metastasis in GC. We also identified that the Thr418 phosphorylation site is crucial for RCC2 ubiquitination at the K377, initiating its degradation in response to ROS. In conclusion, our results indicate that GPx4 acts as an oncogene in GC, and that suppressing GPx4 prevents GC progression and metastasis by promoting ROS-induced RCC2 ubiquitination and degradation.http://www.sciencedirect.com/science/article/pii/S2213231725000321Gastric cancerGPx4RCC2MetastasisROS |
| spellingShingle | Can Hu Jingli Xu Yanqiang Zhang Ruolan Zhang Siwei Pan Jiahui Chen Yan Wang Qianyu Zhao Yuqi Wang Weiwei Zhu Mengxuan Cao Shengjie Zhang Dan Zu Zhiyuan Xu Ji Jing Xiangdong Cheng Inhibition of glutathione peroxidase 4 suppresses gastric cancer peritoneal metastasis via regulation of RCC2 homeostasis Redox Biology Gastric cancer GPx4 RCC2 Metastasis ROS |
| title | Inhibition of glutathione peroxidase 4 suppresses gastric cancer peritoneal metastasis via regulation of RCC2 homeostasis |
| title_full | Inhibition of glutathione peroxidase 4 suppresses gastric cancer peritoneal metastasis via regulation of RCC2 homeostasis |
| title_fullStr | Inhibition of glutathione peroxidase 4 suppresses gastric cancer peritoneal metastasis via regulation of RCC2 homeostasis |
| title_full_unstemmed | Inhibition of glutathione peroxidase 4 suppresses gastric cancer peritoneal metastasis via regulation of RCC2 homeostasis |
| title_short | Inhibition of glutathione peroxidase 4 suppresses gastric cancer peritoneal metastasis via regulation of RCC2 homeostasis |
| title_sort | inhibition of glutathione peroxidase 4 suppresses gastric cancer peritoneal metastasis via regulation of rcc2 homeostasis |
| topic | Gastric cancer GPx4 RCC2 Metastasis ROS |
| url | http://www.sciencedirect.com/science/article/pii/S2213231725000321 |
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