TCF25 serves as a nutrient sensor to orchestrate metabolic adaptation and cell death by enhancing lysosomal acidification under glucose starvation
Summary: Cells adapt to nutrient limitation by activating catabolic and inhibiting anabolic pathways, yet prolonged stress may lead to cell death. How cells orchestrate metabolic adaptation and cell death to nutrient stress is poorly understood. We conduct a genome-wide CRISPR-Cas9 screen to identif...
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Elsevier
2025-09-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S221112472500957X |
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| author | Wenqing Ren Hui Jiang Qianqian Song Yiliang Chen Chenxiao Tang Fang Wang Jing Zhu Jingming Ren Yaxing Zhao Yuan He Jin Cai Tianle Zhang Zhuhong Wang Chenjie Zhu Wen Xue Ai Peng Xiaona Feng Yue Liu Jianqiang Yu Zheng-gang Liu Zhenyu Cai |
| author_facet | Wenqing Ren Hui Jiang Qianqian Song Yiliang Chen Chenxiao Tang Fang Wang Jing Zhu Jingming Ren Yaxing Zhao Yuan He Jin Cai Tianle Zhang Zhuhong Wang Chenjie Zhu Wen Xue Ai Peng Xiaona Feng Yue Liu Jianqiang Yu Zheng-gang Liu Zhenyu Cai |
| author_sort | Wenqing Ren |
| collection | DOAJ |
| description | Summary: Cells adapt to nutrient limitation by activating catabolic and inhibiting anabolic pathways, yet prolonged stress may lead to cell death. How cells orchestrate metabolic adaptation and cell death to nutrient stress is poorly understood. We conduct a genome-wide CRISPR-Cas9 screen to identify regulators in glucose-starvation-induced cell death and find a group of genes in lysosomal pathway is enriched following glucose starvation. We focus on one candidate gene, Transcriptional Factor 25 (TCF25). We find TCF25 enhances lysosomal acidification by targeting V-ATPase, promoting autophagy and ATP generation under glucose starvation. However, prolonged glucose starvation constitutively activates ferritinophagy via TCF25, increasing lysosomal membrane permeability (LMP) and leading to lysosome-dependent cell death (LDCD). Knocking out TCF25 or V-ATPase components prevents cell death. Furthermore, TCF25 deficiency protects mice from hepatic ischemia-reperfusion injury. Our findings identify TCF25 as a crucial nutrient sensor that regulates lysosomal activity, offering potential therapeutic targets for metabolic and ischemic disorders. |
| format | Article |
| id | doaj-art-e15fed82b46d4ca09f5312f146efd44d |
| institution | Kabale University |
| issn | 2211-1247 |
| language | English |
| publishDate | 2025-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj-art-e15fed82b46d4ca09f5312f146efd44d2025-08-23T04:48:04ZengElsevierCell Reports2211-12472025-09-0144911618610.1016/j.celrep.2025.116186TCF25 serves as a nutrient sensor to orchestrate metabolic adaptation and cell death by enhancing lysosomal acidification under glucose starvationWenqing Ren0Hui Jiang1Qianqian Song2Yiliang Chen3Chenxiao Tang4Fang Wang5Jing Zhu6Jingming Ren7Yaxing Zhao8Yuan He9Jin Cai10Tianle Zhang11Zhuhong Wang12Chenjie Zhu13Wen Xue14Ai Peng15Xiaona Feng16Yue Liu17Jianqiang Yu18Zheng-gang Liu19Zhenyu Cai20Tongji University Cancer Center, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai 200072, China; Corresponding author ▪▪▪Tongji University Cancer Center, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai 200072, China; Department of Biochemistry and Molecular Biology, School of Medicine, Tongji University, Shanghai 200331, ChinaTongji University Cancer Center, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai 200072, China; Department of Biochemistry and Molecular Biology, School of Medicine, Tongji University, Shanghai 200331, ChinaTongji University Cancer Center, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai 200072, China; Department of Biochemistry and Molecular Biology, School of Medicine, Tongji University, Shanghai 200331, ChinaTongji University Cancer Center, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai 200072, China; Department of Biochemistry and Molecular Biology, School of Medicine, Tongji University, Shanghai 200331, ChinaTongji University Cancer Center, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai 200072, China; Department of Biochemistry and Molecular Biology, School of Medicine, Tongji University, Shanghai 200331, ChinaTongji University Cancer Center, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai 200072, China; Department of Biochemistry and Molecular Biology, School of Medicine, Tongji University, Shanghai 200331, ChinaTongji University Cancer Center, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai 200072, China; Department of Biochemistry and Molecular Biology, School of Medicine, Tongji University, Shanghai 200331, ChinaTongji University Cancer Center, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai 200072, ChinaTongji University Cancer Center, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai 200072, ChinaTongji University Cancer Center, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai 200072, China; Department of Biochemistry and Molecular Biology, School of Medicine, Tongji University, Shanghai 200331, ChinaTongji University Cancer Center, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai 200072, China; Department of Biochemistry and Molecular Biology, School of Medicine, Tongji University, Shanghai 200331, ChinaTongji University Cancer Center, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai 200072, China; Department of Biochemistry and Molecular Biology, School of Medicine, Tongji University, Shanghai 200331, ChinaDepartment of Biochemistry and Molecular Biology, School of Medicine, Tongji University, Shanghai 200331, ChinaCenter for Nephrology & Metabolomics, Division of Nephrology, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai 200072, ChinaCenter for Nephrology & Metabolomics, Division of Nephrology, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai 200072, ChinaCollege of Pharmacy, Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region, Yinchuan 750004, ChinaCollege of Pharmacy, Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region, Yinchuan 750004, ChinaCollege of Pharmacy, Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region, Yinchuan 750004, ChinaLaboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USATongji University Cancer Center, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai 200072, China; Department of Biochemistry and Molecular Biology, School of Medicine, Tongji University, Shanghai 200331, China; College of Pharmacy, Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region, Yinchuan 750004, China; State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China; Corresponding authorSummary: Cells adapt to nutrient limitation by activating catabolic and inhibiting anabolic pathways, yet prolonged stress may lead to cell death. How cells orchestrate metabolic adaptation and cell death to nutrient stress is poorly understood. We conduct a genome-wide CRISPR-Cas9 screen to identify regulators in glucose-starvation-induced cell death and find a group of genes in lysosomal pathway is enriched following glucose starvation. We focus on one candidate gene, Transcriptional Factor 25 (TCF25). We find TCF25 enhances lysosomal acidification by targeting V-ATPase, promoting autophagy and ATP generation under glucose starvation. However, prolonged glucose starvation constitutively activates ferritinophagy via TCF25, increasing lysosomal membrane permeability (LMP) and leading to lysosome-dependent cell death (LDCD). Knocking out TCF25 or V-ATPase components prevents cell death. Furthermore, TCF25 deficiency protects mice from hepatic ischemia-reperfusion injury. Our findings identify TCF25 as a crucial nutrient sensor that regulates lysosomal activity, offering potential therapeutic targets for metabolic and ischemic disorders.http://www.sciencedirect.com/science/article/pii/S221112472500957XCP: Cell biologyCP: Metabolism |
| spellingShingle | Wenqing Ren Hui Jiang Qianqian Song Yiliang Chen Chenxiao Tang Fang Wang Jing Zhu Jingming Ren Yaxing Zhao Yuan He Jin Cai Tianle Zhang Zhuhong Wang Chenjie Zhu Wen Xue Ai Peng Xiaona Feng Yue Liu Jianqiang Yu Zheng-gang Liu Zhenyu Cai TCF25 serves as a nutrient sensor to orchestrate metabolic adaptation and cell death by enhancing lysosomal acidification under glucose starvation Cell Reports CP: Cell biology CP: Metabolism |
| title | TCF25 serves as a nutrient sensor to orchestrate metabolic adaptation and cell death by enhancing lysosomal acidification under glucose starvation |
| title_full | TCF25 serves as a nutrient sensor to orchestrate metabolic adaptation and cell death by enhancing lysosomal acidification under glucose starvation |
| title_fullStr | TCF25 serves as a nutrient sensor to orchestrate metabolic adaptation and cell death by enhancing lysosomal acidification under glucose starvation |
| title_full_unstemmed | TCF25 serves as a nutrient sensor to orchestrate metabolic adaptation and cell death by enhancing lysosomal acidification under glucose starvation |
| title_short | TCF25 serves as a nutrient sensor to orchestrate metabolic adaptation and cell death by enhancing lysosomal acidification under glucose starvation |
| title_sort | tcf25 serves as a nutrient sensor to orchestrate metabolic adaptation and cell death by enhancing lysosomal acidification under glucose starvation |
| topic | CP: Cell biology CP: Metabolism |
| url | http://www.sciencedirect.com/science/article/pii/S221112472500957X |
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