# FSP1 and histone deacetylases suppress cancer persister cell ferroptosis

## TL;DR

This study shows that FSP1 and histone deacetylases help cancer persister cells resist a type of cell death called ferroptosis.

## Contribution

The study identifies FSP1 and histone deacetylase inhibition as novel strategies to sensitize persister cells to ferroptosis.

## Key findings

- Persister cells surviving GPX4 inhibition rely on residual FSP1 for survival.
- Histone deacetylase inhibitors increase reactive oxygen species and sensitize persister cells to GPX4 inhibition.
- Persister cells down-regulate oxidative phosphorylation to resist ferroptosis.

## Abstract

Cancer persister cells which survive oncogene targeted therapies are sensitized to ferroptosis, but mechanistic understanding of this vulnerability remains limited. Here, we found that while levels of iron, glutathione, and various ferroptosis-suppressing enzymes vary among persister cell types, ferroptosis suppressor protein 1 (FSP1) is down-regulated in multiple persister cell types, and persister cells which survive glutathione peroxidase 4 (GPX4) inhibition rely on residual FSP1 to survive. Furthermore, persister cells which survive GPX4 inhibition down-regulate oxidative phosphorylation, a key source of mitochondrial reactive oxygen species which are required for persister cell ferroptosis. We also found that persister cell treatment with histone deacetylase inhibitors induces reactive oxygen species and sensitizes multiple persister cell types to GPX4 inhibition. Together, these findings reveal that FSP1 and histone deacetylases suppress persister cell ferroptosis.

Drug-tolerant cancer persister cells can be sensitized to ferroptotic death by FSP1 or histone deacetylase inhibitors.