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

Wenqing Ren1, Hui Jiang2, Qianqian Song2

  • 1Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200072, China.

Cell Reports
|August 22, 2025
PubMed

Insights

Transcriptional Factor 25 (TCF25) regulates cell death during nutrient stress by controlling lysosomal activity. Inhibiting TCF25 protects against cell death and organ injury, offering therapeutic potential.

Area of Science:

  • Cell Biology
  • Metabolism
  • Molecular Biology

Background:

  • Cells adapt to nutrient limitation via metabolic pathway shifts.
  • Prolonged nutrient stress can induce cell death, but regulatory mechanisms remain unclear.

Purpose of the Study:

  • To identify key regulators of glucose-starvation-induced cell death.
  • To elucidate the role of Transcriptional Factor 25 (TCF25) in cellular response to nutrient stress.

Main Methods:

  • Genome-wide CRISPR-Cas9 screening to identify genetic regulators.
  • Analysis of lysosomal pathway gene enrichment under glucose starvation.
  • Investigation of TCF25 function in cellular metabolism and cell death.

Main Results:

  • A screen identified lysosomal pathway genes involved in glucose starvation.
  • TCF25 enhances lysosomal acidification and ATP generation via V-ATPase.
  • Prolonged starvation activates TCF25-mediated ferritinophagy, increasing lysosomal membrane permeability and causing cell death.
  • TCF25 or V-ATPase knockout prevents cell death.
  • TCF25 deficiency protects mice from hepatic ischemia-reperfusion injury.

Conclusions:

  • TCF25 acts as a critical nutrient sensor modulating lysosomal function.
  • TCF25 regulates both adaptive responses (autophagy) and cell death (ferritinophagy, LDCD) under nutrient stress.
  • TCF25 inhibition presents a potential therapeutic strategy for metabolic and ischemic diseases.
Keywords:
CP: Cell biologyCP: MetabolismTCF25cell deathglucose starvationlysosomemetabolic adaptation

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