Ferroptosis & regulated cell death
Cells can die in several programmed ways. Beyond the classic apoptosis, ferroptosis kills through iron-driven fat oxidation, and drug-resistant, mesenchymal cancer cells turn out to be unusually prone to it.
Ferroptosis is iron-dependent lipid peroxidation restrained by GPX4 (using glutathione from the cystine transporter SLC7A11/xCT) and by FSP1. Therapy-persistent, mesenchymal, and dedifferentiated cancer cells depend on GPX4; radiation and some immunotherapies act partly via ferroptosis. Necroptosis (RIPK3/MLKL) and pyroptosis (gasdermins) are inflammatory death modes that can be immunogenic. No ferroptosis inducer is approved; GPX4 inhibitors lack drug-like properties, so xCT inhibition, cyst(e)inase, and sulfasalazine repurposing are the clinical routes.
In one picture
Ferroptosis is rust. Iron plus oxygen eats through the cell's membranes unless an antioxidant crew (GPX4) keeps repainting them. Cells that changed shape to dodge chemotherapy have thinner paint.
Diagram
top- xCT inhibitors, cyst(e)inase, sulfasalazine repurposing (early trials)
- Radiotherapy and IFN-γ from T cells induce lipid peroxidation
- BH3 mimetics (venetoclax) exploit apoptosis; MCL-1 inhibitors in development
- Persister-cell targeting after EGFR/ALK inhibitors (preclinical)
Notes
top- Leading programmes: Stockwell (Columbia, coined ferroptosis); Dixon (Stanford); Schreiber (Broad) on persister-cell GPX4 dependence; Jiang (MSK) on ferroptosis in immunotherapy.