ESCRT-III-mediated membrane repair in cell death and tumor resistance

The plasma membrane is made of glycerophospholipids that separate the inner and outer parts of the cell. Under physiological conditions, it acts as a barrier and gatekeeper to protect cells from the environment. In pathological situations, it undergoes structural and functional changes, resulting in cell damage. Indeed, plasma membrane damage caused by various stresses (e.g., hypoxia, nutritional deficiencies, ultraviolet radiation, and chemotherapeutic agents) is one of the hallmarks of cell death. Phosphatidylserine exposure and plasma membrane blebbing usually occurs in apoptotic cells, while necrotic cells lose the integrity of the plasma membrane and thereby release intracellular damage-associated molecular patterns. In contrast, the endosomal sorting complex required for transport-III (ESCRT-III), an evolutionarily conserved protein complex with membrane fission machinery, plays a key role in the repair of damaged plasma membranes in various types of regulated cell death, such as necroptosis, pyroptosis, and ferroptosis. These emerging findings indicate that ESCRT-III is a potential target to overcome drug resistance during tumor therapy.