biorxiv2026-10-23score 96
ANO6 scaffolds ER-mitochondria contacts that hide peroxidizable lipids from ferroptosis
Yang, Yan and colleagues report that ANO6, better known as a plasma-membrane phospholipid scramblase, works at mitochondria-associated ER membranes as a conformational scaffold. It assembles a vimentin-ANO6-VAPB-PTPIP51 tether that tightens ER-mitochondria coupling and routes polyunsaturated phospholipids into cytoplasmic lipid droplets. That spatial sequestration shields bilayer lipids from ferroptotic peroxidation in chemoresistant breast cancer. Niclosamide or scaffold-dead ANO6 (D703R) collapses the compartment and resensitizes tumors to ferroptosis, including with GPX4 inhibition. The abstract does not name a labile Fe2+ pool or an iron-sulfur cluster. Ferroptosis here is iron-dependent lipid peroxidation of PUFA phospholipids, inferred from the death mode and from RSL3, not from a measured metal site.
