Arsenic inducible islet β-cell dysfunction and ferroptosis through m6A-YTHDF2-dependent CHAC1 enhancement
Arsenic, recognized as an environmental and food contaminant, has been linked to the dysfunction of islet β-cells, the primary lesions in type 2 diabetes (T2D). Ferroptosis, a regulated cell death pathway dependent on GPX4, has been implicated in arsenic-induced β-cell dysfunction. However, the unde...
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Elsevier
2025-01-01
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| Series: | Ecotoxicology and Environmental Safety |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0147651324015550 |
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| author | Tianming Qiu Jingyuan Zhang Jinwei Song Chenbing Wu Xiaofeng Yao Ningning Wang Guang Yang Jie Bai Li Lv Xiance Sun |
| author_facet | Tianming Qiu Jingyuan Zhang Jinwei Song Chenbing Wu Xiaofeng Yao Ningning Wang Guang Yang Jie Bai Li Lv Xiance Sun |
| author_sort | Tianming Qiu |
| collection | DOAJ |
| description | Arsenic, recognized as an environmental and food contaminant, has been linked to the dysfunction of islet β-cells, the primary lesions in type 2 diabetes (T2D). Ferroptosis, a regulated cell death pathway dependent on GPX4, has been implicated in arsenic-induced β-cell dysfunction. However, the underlying molecular mechanisms remain unclear. GPX4 activity is significantly modulated by glutathione levels. In this study, we demonstrate that arsenic inhibits GPX4 expression by upregulating the expression of glutathione-specific γ-glutamylcyclotransferase 1 (CHAC1) (>2-fold in vivo and 1.5-fold in vitro). Conversely, arsenic does not affect the expression of the glutathione-cysteine ligase catalytic subunit (GCLC), which is crucial for glutathione synthesis. Notably, CHAC1 knockdown significantly ameliorated arsenic-induced β-cell dysfunction and ferroptosis. N6-methyladenosine (m6A) plays a crucial role in the post-transcriptional modification of mRNA. Arsenic treatment downregulated the expression of methyltransferases METTL3/14 (approximately 0.5-fold), and overexpression of METTL3 alleviated arsenic-induced β-cell dysfunction and ferroptosis. The m6A modification site on CHAC1 was identified, and RIP assays confirmed that arsenic treatment inhibited the interaction between METTL3/YTHDF2 and CHAC1. Furthermore, METTL3 overexpression reduced the half-life of CHAC1 mRNA (almost 0.5-fold). This study uncovers a novel mechanism by which arsenic modulates CHAC1 and ferroptosis through m6A in β-cell dysfunction, highlighting potential therapeutic targets for arsenic-related T2D. |
| format | Article |
| id | doaj-art-cab0dd2151454e23b4923571a8e2bd98 |
| institution | Kabale University |
| issn | 0147-6513 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Ecotoxicology and Environmental Safety |
| spelling | doaj-art-cab0dd2151454e23b4923571a8e2bd982025-01-23T05:25:43ZengElsevierEcotoxicology and Environmental Safety0147-65132025-01-01289117479Arsenic inducible islet β-cell dysfunction and ferroptosis through m6A-YTHDF2-dependent CHAC1 enhancementTianming Qiu0Jingyuan Zhang1Jinwei Song2Chenbing Wu3Xiaofeng Yao4Ningning Wang5Guang Yang6Jie Bai7Li Lv8Xiance Sun9Department of Occupational and Environmental Health, School of Public Health, Dalian Medical University, No. 9 West Section Lvshun South Road, Dalian 116044, PR ChinaDepartment of Occupational and Environmental Health, School of Public Health, Dalian Medical University, No. 9 West Section Lvshun South Road, Dalian 116044, PR ChinaDepartment of Occupational and Environmental Health, School of Public Health, Dalian Medical University, No. 9 West Section Lvshun South Road, Dalian 116044, PR ChinaPreventive Medicine Laboratory, School of Public Health, Dalian Medical University, No. 9 West Section Lvshun South Road, 116044, PR ChinaDepartment of Occupational and Environmental Health, School of Public Health, Dalian Medical University, No. 9 West Section Lvshun South Road, Dalian 116044, PR ChinaDepartment of Nutrition and Food Safety, School of Public Health, Dalian Medical University, No. 9 West Section Lvshun South Road, Dalian 116044, PR ChinaDepartment of Nutrition and Food Safety, School of Public Health, Dalian Medical University, No. 9 West Section Lvshun South Road, Dalian 116044, PR ChinaPreventive Medicine Laboratory, School of Public Health, Dalian Medical University, No. 9 West Section Lvshun South Road, 116044, PR ChinaDepartment of Pathology, the Second Affiliated Hospital of Dalian Medical University, No. 467 Zhongshan Road, Dalian 116023, PR China; Correspondence to: Department of Pathology, the Second Affiliated Hospital of Dalian Medical University, PR China.Department of Occupational and Environmental Health, School of Public Health, Dalian Medical University, No. 9 West Section Lvshun South Road, Dalian 116044, PR China; Global Health Research Center, Dalian Medical University, No. 9 West Section Lvshun South Road, Dalian 116044, PR China; Correspondence to: Department of Occupational and Environmental Health, Global Health Research Center, School of Public Health, Dalian Medical University, Dalian 166044, PR China.Arsenic, recognized as an environmental and food contaminant, has been linked to the dysfunction of islet β-cells, the primary lesions in type 2 diabetes (T2D). Ferroptosis, a regulated cell death pathway dependent on GPX4, has been implicated in arsenic-induced β-cell dysfunction. However, the underlying molecular mechanisms remain unclear. GPX4 activity is significantly modulated by glutathione levels. In this study, we demonstrate that arsenic inhibits GPX4 expression by upregulating the expression of glutathione-specific γ-glutamylcyclotransferase 1 (CHAC1) (>2-fold in vivo and 1.5-fold in vitro). Conversely, arsenic does not affect the expression of the glutathione-cysteine ligase catalytic subunit (GCLC), which is crucial for glutathione synthesis. Notably, CHAC1 knockdown significantly ameliorated arsenic-induced β-cell dysfunction and ferroptosis. N6-methyladenosine (m6A) plays a crucial role in the post-transcriptional modification of mRNA. Arsenic treatment downregulated the expression of methyltransferases METTL3/14 (approximately 0.5-fold), and overexpression of METTL3 alleviated arsenic-induced β-cell dysfunction and ferroptosis. The m6A modification site on CHAC1 was identified, and RIP assays confirmed that arsenic treatment inhibited the interaction between METTL3/YTHDF2 and CHAC1. Furthermore, METTL3 overexpression reduced the half-life of CHAC1 mRNA (almost 0.5-fold). This study uncovers a novel mechanism by which arsenic modulates CHAC1 and ferroptosis through m6A in β-cell dysfunction, highlighting potential therapeutic targets for arsenic-related T2D.http://www.sciencedirect.com/science/article/pii/S0147651324015550Arsenicβ-cellFerroptosisCHAC1N6-methyladenosine |
| spellingShingle | Tianming Qiu Jingyuan Zhang Jinwei Song Chenbing Wu Xiaofeng Yao Ningning Wang Guang Yang Jie Bai Li Lv Xiance Sun Arsenic inducible islet β-cell dysfunction and ferroptosis through m6A-YTHDF2-dependent CHAC1 enhancement Ecotoxicology and Environmental Safety Arsenic β-cell Ferroptosis CHAC1 N6-methyladenosine |
| title | Arsenic inducible islet β-cell dysfunction and ferroptosis through m6A-YTHDF2-dependent CHAC1 enhancement |
| title_full | Arsenic inducible islet β-cell dysfunction and ferroptosis through m6A-YTHDF2-dependent CHAC1 enhancement |
| title_fullStr | Arsenic inducible islet β-cell dysfunction and ferroptosis through m6A-YTHDF2-dependent CHAC1 enhancement |
| title_full_unstemmed | Arsenic inducible islet β-cell dysfunction and ferroptosis through m6A-YTHDF2-dependent CHAC1 enhancement |
| title_short | Arsenic inducible islet β-cell dysfunction and ferroptosis through m6A-YTHDF2-dependent CHAC1 enhancement |
| title_sort | arsenic inducible islet β cell dysfunction and ferroptosis through m6a ythdf2 dependent chac1 enhancement |
| topic | Arsenic β-cell Ferroptosis CHAC1 N6-methyladenosine |
| url | http://www.sciencedirect.com/science/article/pii/S0147651324015550 |
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