2. Academic Validation
  3. TCF25 serves as a nutrient sensor to orchestrate metabolic adaptation and cell death by enhancing lysosomal acidification under glucose starvation

TCF25 serves as a nutrient sensor to orchestrate metabolic adaptation and cell death by enhancing lysosomal acidification under glucose starvation

  • Cell Rep. 2025 Aug 21;44(9):116186. doi: 10.1016/j.celrep.2025.116186.
Wenqing Ren 1,  Hui Jiang 2,  Qianqian Song 2,  Yiliang Chen 2,  Chenxiao Tang 2,  Fang Wang 2,  Jing Zhu 2,  Jingming Ren 2,  Yaxing Zhao 3,  Yuan He 3,  Jin Cai 2,  Tianle Zhang 2,  Zhuhong Wang 2,  Chenjie Zhu 4,  Wen Xue 5,  Ai Peng 5,  Xiaona Feng 6,  Yue Liu 6,  Jianqiang Yu 6,  Zheng-Gang Liu 7,  Zhenyu Cai 8
Affiliations

Affiliations

  • 1 Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200072, China. Electronic address: 2205378@tongji.edu.cn.
  • 2 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, China.
  • 3 Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200072, China.
  • 4 Department of Biochemistry and Molecular Biology, School of Medicine, Tongji University, Shanghai 200331, China.
  • 5 Center for Nephrology & Metabolomics, Division of Nephrology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200072, China.
  • 6 College of Pharmacy, Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region, Yinchuan 750004, China.
  • 7 Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • 8 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, 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. Electronic address: drcaizhenyu@tongji.edu.cn.
PMID: 40844875 DOI: 10.1016/j.celrep.2025.116186
Abstract

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.

Keywords

CP: Cell biology; CP: Metabolism; TCF25; cell death; glucose starvation; lysosome; metabolic adaptation.

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