FSP1 and histone deacetylases suppress cancer persister cell ferroptosis

Cancer persister cells populate minimal residual disease and contribute to acquired drug resistance. We previously discovered that persister cells are sensitized to ferroptosis. However, our understanding of this emergent persister cell vulnerability remains limited, impeding ferroptosis drug development efforts. Here, we sought to understand key factors which govern persister cell ferroptosis to inform combinatorial treatment strategies. We found that persister cells can downregulate oxidative phosphorylation, a key source of reactive oxygen species, to avoid death from GPX4 inhibition. However, this can be overcome by pretreatment with clinically available histone deacetylase inhibitors which induce reactive oxygen species in persister cells and synergize with GPX4 inhibition. Furthermore, we found that while levels of iron, glutathione, and antioxidant genes are not universally dysregulated in persister cells, persister cells consistently downregulate alternative ferroptosis suppressor FSP1 and rely upon residual FSP1 to survive GPX4 inhibition. These findings reveal new strategies to eliminate persister cells by combining GPX4 inhibitors with histone deacetylase or FSP1 inhibitors.