Inhibition of eEF2 kinase ameliorates hepatic injury induced by ACR through regulation of the MAPK pathway
Background and aims: Acrylamide (ACR) induces hepatotoxicity, yet its underlying mechanisms remain incompletely understood. Our prior proteomic analysis of serum from occupationally ACR-exposed individuals identified significantly elevated levels of eukaryotic elongation factor 2 (eEF2). Given that...
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Elsevier
2025-09-01
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| Series: | Ecotoxicology and Environmental Safety |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0147651325012436 |
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| author | Zhi-Ming Li Xiao-Li Wang Hong-Wei Yao Guo-Bing Yu Xin-Yu Wang Ru-Nan Zhang Xiao-Xiao Hao Wei-Wei Ma Yu-Meng Xu Hong-Qiu Li Ya-Ting Lei Fang-Fang Zhao Cui-Ping Yu Yong-Hui Wu Yu-Lin Pan Sheng-Yuan Wang |
| author_facet | Zhi-Ming Li Xiao-Li Wang Hong-Wei Yao Guo-Bing Yu Xin-Yu Wang Ru-Nan Zhang Xiao-Xiao Hao Wei-Wei Ma Yu-Meng Xu Hong-Qiu Li Ya-Ting Lei Fang-Fang Zhao Cui-Ping Yu Yong-Hui Wu Yu-Lin Pan Sheng-Yuan Wang |
| author_sort | Zhi-Ming Li |
| collection | DOAJ |
| description | Background and aims: Acrylamide (ACR) induces hepatotoxicity, yet its underlying mechanisms remain incompletely understood. Our prior proteomic analysis of serum from occupationally ACR-exposed individuals identified significantly elevated levels of eukaryotic elongation factor 2 (eEF2). Given that eEF2 activity is regulated by its phosphorylation status, which is solely mediated by eukaryotic elongation factor 2 kinase (eEF2K), we investigated the role of eEF2K in ACR-induced hepatic injury. Methods: eEF2K gene knockout (eEF2K-/-) mice were used to assess the impact of eEF2K ablation on ACR-induced hepatotoxicity. Downstream mechanisms were explored by liver metabolomics and Western blot analysis. Results: ACR exposure significantly increased hepatic eEF2K expression and eEF2 phosphorylation (P < 0.05). eEF2K knockout (KO) significantly attenuated ACR-induced hepatic injury, indicated by improved histopathology, reduced serum ALT/AST levels, and restored liver coefficients (P < 0.05). Metabolomics revealed that eEF2K ablation counteracted ACR-induced perturbations in sphingolipid metabolism. Mechanistically, eEF2K deficiency normalized sphingolipid metabolism and prevented MAPK signaling dysregulation induced by ACR. Conclusions: This study identifies eEF2K as a key regulator in ACR-induced hepatic injury. ACR exposure promotes MAPK signaling hyperactivation via eEF2K-dependent dysregulation of sphingolipid metabolism, contributing to hepatic injury. Inhibition of eEF2K attenuates ACR-induced hepatic injury. Inhibition of eEF2K represents a novel therapeutic strategy for mitigating ACR-associated hepatic injury. |
| format | Article |
| id | doaj-art-97cb8032ca0849a6be3ad3ef23c0c375 |
| institution | Kabale University |
| issn | 0147-6513 |
| language | English |
| publishDate | 2025-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Ecotoxicology and Environmental Safety |
| spelling | doaj-art-97cb8032ca0849a6be3ad3ef23c0c3752025-08-22T04:54:46ZengElsevierEcotoxicology and Environmental Safety0147-65132025-09-0130311889810.1016/j.ecoenv.2025.118898Inhibition of eEF2 kinase ameliorates hepatic injury induced by ACR through regulation of the MAPK pathwayZhi-Ming Li0Xiao-Li Wang1Hong-Wei Yao2Guo-Bing Yu3Xin-Yu Wang4Ru-Nan Zhang5Xiao-Xiao Hao6Wei-Wei Ma7Yu-Meng Xu8Hong-Qiu Li9Ya-Ting Lei10Fang-Fang Zhao11Cui-Ping Yu12Yong-Hui Wu13Yu-Lin Pan14Sheng-Yuan Wang15Department of Occupational Health, Public Health College, Harbin Medical University, Harbin, PR ChinaDepartment of Occupational Health, Public Health College, Harbin Medical University, Harbin, PR ChinaDepartment of Occupational Health, Public Health College, Harbin Medical University, Harbin, PR ChinaDepartment of Occupational Health, Public Health College, Harbin Medical University, Harbin, PR ChinaDepartment of Occupational Health, Public Health College, Harbin Medical University, Harbin, PR ChinaNational Key Discipline, Department of Nutrition and Food Hygiene, Harbin Medical University, Harbin, PR ChinaDepartment of Occupational Health, Public Health College, Harbin Medical University, Harbin, PR ChinaHarbin Railway Center for Disease Control and Prevention, Harbin, PR ChinaDepartment of Occupational Health, Public Health College, Harbin Medical University, Harbin, PR ChinaDepartment of Occupational Health, Public Health College, Harbin Medical University, Harbin, PR ChinaDepartment of Occupational Health, Public Health College, Harbin Medical University, Harbin, PR ChinaDepartment of Occupational Health, Public Health College, Harbin Medical University, Harbin, PR ChinaDepartment of Occupational Health, Public Health College, Harbin Medical University, Harbin, PR ChinaDepartment of Occupational Health, Public Health College, Harbin Medical University, Harbin, PR China; Correspondence to: Department of Occupational Health, Public Health College, Harbin Medical University, 157 Baojian Road, Nan gang District, Harbin 150086, PR China.Department of Occupational Health, Public Health College, Harbin Medical University, Harbin, PR China; Correspondence to: Department of Occupational Health, Public Health College, Harbin Medical University, 157 Baojian Road, Nan gang District, Harbin 150086, PR China.Department of Occupational Health, Public Health College, Harbin Medical University, Harbin, PR China; Correspondence to: Department of Occupational Health, Public Health College, Harbin Medical University, 157 Baojian Road, Nan gang District, Harbin 150086, PR China.Background and aims: Acrylamide (ACR) induces hepatotoxicity, yet its underlying mechanisms remain incompletely understood. Our prior proteomic analysis of serum from occupationally ACR-exposed individuals identified significantly elevated levels of eukaryotic elongation factor 2 (eEF2). Given that eEF2 activity is regulated by its phosphorylation status, which is solely mediated by eukaryotic elongation factor 2 kinase (eEF2K), we investigated the role of eEF2K in ACR-induced hepatic injury. Methods: eEF2K gene knockout (eEF2K-/-) mice were used to assess the impact of eEF2K ablation on ACR-induced hepatotoxicity. Downstream mechanisms were explored by liver metabolomics and Western blot analysis. Results: ACR exposure significantly increased hepatic eEF2K expression and eEF2 phosphorylation (P < 0.05). eEF2K knockout (KO) significantly attenuated ACR-induced hepatic injury, indicated by improved histopathology, reduced serum ALT/AST levels, and restored liver coefficients (P < 0.05). Metabolomics revealed that eEF2K ablation counteracted ACR-induced perturbations in sphingolipid metabolism. Mechanistically, eEF2K deficiency normalized sphingolipid metabolism and prevented MAPK signaling dysregulation induced by ACR. Conclusions: This study identifies eEF2K as a key regulator in ACR-induced hepatic injury. ACR exposure promotes MAPK signaling hyperactivation via eEF2K-dependent dysregulation of sphingolipid metabolism, contributing to hepatic injury. Inhibition of eEF2K attenuates ACR-induced hepatic injury. Inhibition of eEF2K represents a novel therapeutic strategy for mitigating ACR-associated hepatic injury.http://www.sciencedirect.com/science/article/pii/S0147651325012436AcrylamideEEF2KHepatic injurySphingolipidsMAPK signaling pathway |
| spellingShingle | Zhi-Ming Li Xiao-Li Wang Hong-Wei Yao Guo-Bing Yu Xin-Yu Wang Ru-Nan Zhang Xiao-Xiao Hao Wei-Wei Ma Yu-Meng Xu Hong-Qiu Li Ya-Ting Lei Fang-Fang Zhao Cui-Ping Yu Yong-Hui Wu Yu-Lin Pan Sheng-Yuan Wang Inhibition of eEF2 kinase ameliorates hepatic injury induced by ACR through regulation of the MAPK pathway Ecotoxicology and Environmental Safety Acrylamide EEF2K Hepatic injury Sphingolipids MAPK signaling pathway |
| title | Inhibition of eEF2 kinase ameliorates hepatic injury induced by ACR through regulation of the MAPK pathway |
| title_full | Inhibition of eEF2 kinase ameliorates hepatic injury induced by ACR through regulation of the MAPK pathway |
| title_fullStr | Inhibition of eEF2 kinase ameliorates hepatic injury induced by ACR through regulation of the MAPK pathway |
| title_full_unstemmed | Inhibition of eEF2 kinase ameliorates hepatic injury induced by ACR through regulation of the MAPK pathway |
| title_short | Inhibition of eEF2 kinase ameliorates hepatic injury induced by ACR through regulation of the MAPK pathway |
| title_sort | inhibition of eef2 kinase ameliorates hepatic injury induced by acr through regulation of the mapk pathway |
| topic | Acrylamide EEF2K Hepatic injury Sphingolipids MAPK signaling pathway |
| url | http://www.sciencedirect.com/science/article/pii/S0147651325012436 |
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