# ERM Inhibition Confers Ferroptosis Resistance through ROS‐Induced NRF2 Signaling

## TL;DR

This study shows that inhibiting ERM proteins can protect cells from ferroptosis by triggering a redox response involving ROS and NRF2.

## Contribution

ERM proteins are newly identified as regulators of ferroptosis through ROS-NRF2 signaling.

## Key findings

- ERM inhibition reduces ferroptosis by increasing ROS and activating NRF2.
- NRF2 activation induces HMOX1, which limits lipid peroxidation and protects cells.
- ERM inhibitors act as pro-oxidants that paradoxically confer ferroptosis resistance.

## Abstract

Ferroptosis is an iron‐dependent form of programmed cell death governed by redox homeostasis. Although Ezrin, Radixin, and Moesin (ERM) proteins are established membrane‐actin cytoskeleton linkers, their role in ferroptosis remains unexplored. Here, ERM proteins are identified as modulators of erastin‐induced ferroptosis. In human fibrosarcoma HT‐1080 cells, pharmacological inhibition of ERM phosphorylation, knockdown of individual ERM members, or overexpression of a phospho‐deficient Ezrin mutant (T567A) consistently attenuated ferroptosis, whereas wild‐type ERM overexpression enhances ferroptosis susceptibility. Mechanistically, ERM inhibition leads to F‐actin depolymerization accompanied by a modest rise in reactive oxygen species (ROS). F‐actin stabilization prevents this ROS surge and restores ferroptotic sensitivity, whereas its depolymerization mimics the protective effect of ERM inhibition. ROS elevation triggers KEAP1 degradation, stabilizing NRF2 and promoting its nuclear translocation. Activated nuclear NRF2 induces antioxidant genes, particularly HMOX1, a key effector of heme catabolism that enhances redox buffering and limits lipid peroxidation, ultimately conferring resistance to ferroptosis. The protective effects of ERM inhibition are further validated in ferroptosis‐relevant ex vivo and in vivo models. Notably, other pro‐oxidants similarly attenuate ferroptosis at appropriate concentrations. Together, these results establish ERM proteins as regulators of ferroptosis and reveal an underappreciated group of ferroptosis inhibitors that engage ROS‐NRF2‐mediated redox‐adaptation.

ERM inhibition disrupts ERM‐actin interactions, elevating ROS and triggering KEAP1 degradation, which stabilizes and activates NRF2. Nuclear NRF2 induces cytoprotective genes, notably HMOX1, enhancing redox buffering and suppressing lipid peroxidation to resist erastin‐induced ferroptosis. ERM inhibitors thus act as pro‐oxidants that paradoxically promote ferroptosis resistance, with protective effects observed in ex vivo and in vivo models.