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

## TL;DR

TCF25 helps cells manage energy during glucose shortage but can also cause cell death if the stress continues.

## Contribution

TCF25 is identified as a nutrient sensor that regulates lysosomal activity and cell death under glucose starvation.

## Key findings

- TCF25 enhances lysosomal acidification and autophagy during glucose starvation.
- Prolonged glucose starvation leads to TCF25-mediated ferritinophagy and lysosome-dependent cell death.
- TCF25 deficiency protects mice from hepatic ischemia-reperfusion injury.

## 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.

Ren et al. demonstrate that TCF25 enhances lysosomal acidification via
V-ATPase during glucose starvation, promoting autophagy to maintain energy
balance. However, prolonged starvation makes TCF25-mediated lysosomal-autophagic
activity crucial for ferritinophagy, ultimately causing lysosome-dependent cell
death.