Abstract
Ferroptosis is a form of regulated cell death that is triggered by iron accumulation and lipid peroxidation. Although plasma membrane injuries represent an important event in cell death, the impact of membrane repair mechanisms on ferroptosis remains unidentified. Here, we provide the first evidence that membrane repair dependent on endosomal sorting complexes required for transport (ESCRT)-III negatively regulates ferroptotic cancer cell death. The accumulation of ESCRT-III subunits (e.g., CHMP5 and CHMP6) in the plasma membrane are increased by classical ferroptosis activators (e.g., erastin and RSL3), which relies on endoplasmic reticulum stress and calcium influx. Importantly, the knockdown of CHMP5 or CHMP6 by RNAi sensitizes human cancer cells (e.g., PANC1 and HepG2) to lipid peroxidation-mediated ferroptosis in vitro and in vivo. These findings suggest that ESCRT-III confers resistance to ferroptotic cell death, allowing cell survival under stress conditions.