ESCRT-III-dependent membrane repair blocks ferroptosis

Area of Science:

• Cell Biology
• Cancer Research
• Molecular Biology

Background:

• Ferroptosis is a regulated cell death pathway involving iron and lipid peroxidation.
• Plasma membrane integrity is crucial in cell death, but its link to ferroptosis is unknown.
• The role of membrane repair mechanisms in ferroptosis remains largely unexplored.

Purpose of the Study:

• To investigate the impact of membrane repair mechanisms on ferroptosis.
• To determine if the endosomal sorting complexes required for transport (ESCRT)-III pathway influences ferroptotic cancer cell death.

Main Methods:

• Utilized classical ferroptosis activators (erastin, RSL3) to induce cell death.
• Examined the accumulation of ESCRT-III subunits (CHMP5, CHMP6) at the plasma membrane.
• Employed RNA interference (RNAi) to knockdown CHMP5 and CHMP6 in human cancer cells (PANC1, HepG2).
• Assessed ferroptosis sensitivity in vitro and in vivo.

Main Results:

• Ferroptosis activators increased ESCRT-III subunit accumulation at the plasma membrane, dependent on endoplasmic reticulum stress and calcium influx.
• Knockdown of CHMP5 or CHMP6 significantly sensitized human cancer cells to ferroptosis.
• ESCRT-III subunit depletion enhanced lipid peroxidation-mediated cell death in vitro and in vivo.

Conclusions:

• The ESCRT-III pathway negatively regulates ferroptotic cancer cell death.
• ESCRT-III confers resistance to ferroptosis, promoting cancer cell survival under stress.
• Targeting ESCRT-III may represent a novel strategy to enhance ferroptosis-based cancer therapies.