Sterols in ferroptosis: from molecular mechanisms to therapeutic strategies

Ferroptosis, a novel cell death mode driven by iron-dependent phospholipid (PL) peroxidation, has emerged as a promising therapeutic strategy for the treatments of cancer, cardiovascular diseases, and ischemic-reperfusion injury (IRI). PL peroxidation, the key process of ferroptosis, requires polyunsaturated fatty acid (PUFA)-containing PLs (PL-PUFAs) as substrates, undergoing a chain reaction with iron and oxygen. Cells prevent ferroptosis by maintaining a homeostatic equilibrium among substrates, processes, and detoxification of PL peroxidation. Sterols, lipids abundant in cell membranes, directly participate in PL peroxidation and influence ferroptosis sensitivity. Sterol metabolism also plays a key role in ferroptosis, and targeting sterols presents significant potential for treating numerous ferroptosis-associated disorders. This review elucidates the fundamental mechanisms of ferroptosis, emphasizing how sterols modulate this process and their therapeutic potential.