FIGURE 4.

Lipid droplets (LDs) sensitize drug-resistant cancer cells to ferroptosis. The acquisition of multidrug resistant states in cancer cells is accompanied by widespread metabolic remodeling and activation of various signaling pathways, including increased lipid uptake, progesterone receptor membrane component 1 (PGRMC1) overexpression and activation of the hypoxia-inducible factor 2 alpha (HIF-2α)/hypoxia-inducible LD-associated protein (HILPDA) axis, which promote the accumulation of polyunsaturated fatty acid (PUFA)-enriched triglycerides and cholesteryl esters stored within LDs. These LDs may contribute through lipolysis and lipophagy to the enrichment of membrane phospholipids with PUFAs (PUFA-PLs). PUFA-PLs are easily oxidized during oxidative stress giving rise to various oxidized phospholipid species (ox-PUFA-PLs) that impair membrane function and may further propagate membrane lipid peroxidation, which can sensitize cells to ferroptosis.