Figure 1.
Phenotypic heterogeneity of small cell lung cancer (SCLC): Heterogenous SCLC tumors contain non-neuroendocrine (non-NE) and neuroendocrine (NE) cells. Non-NE cell membranes are characterized by a high arachidonic acid (AA) and adrenic acid (AdA) phospholipid and ether-linked polyunsaturated fatty acid (PUFA) phospholipid content prone to be peroxidized during ferroptosis. Acyl-CoA synthetase long-chain family member 4 (ACSL4) and lysophosphatidylcholine acyltransferase 3 (LPCAT3) are crucial for the synthesis of AA and AdA containing phospholipids and alkylglycerone phosphate synthase (AGPS) and 1-acylglycerol-3-phosphate O-acyltransferase 3 (AGPAT3) catalyze ether phospholipid synthesis from Acyl-Coenzyme A (Acyl-CoA) and are highly expressed in non-NE SCLC cells. Peroxidation of membrane lipids is counteracted by glutathione peroxidase 4 (GPX4) reducing lipid peroxides (L-OOH) to their respective lipid alcohol (L-OH) while oxidizing glutathione (GSH) to glutathione disulfide (GSSG) thereby preventing ferroptosis. NE SCLC cells present with a lipidome less prone to ferroptosis-induced lipid peroxidation and are highly dependent on the thioredoxin (TRX) redox pathway. Here, reactive oxygen (ROS) species such as hydrogen peroxide (H2O2) as well as lipid peroxides are reduced respectively by peroxiredoxins (PRDX) using TRX as a redox equivalent, which is restored by thioredoxin reductases (TRXRD). Inhibition of the thioredoxin pathways results in ROS-dependent cell death in NE SCLC. The scheme was drawn using fully licensed Biorender.com