Fig. 7. SCLC non-NE/NE subtypes segregate by lipid ROS/ROS vulnerability.

Heterogeneous SCLC tumors contain NE cells expressing high levels of ASCL1 and low levels of REST1 and non-NE cells with an inverse expression pattern. Upon induction of ferroptosis by BSO, non-NE cells die due to excessive lipid ROS accumulation. NE cells, in turn, undergo ROS-dependent cell death upon TRX pathway inhibition. Surviving cellular fractions in both single treatment arms can transdifferentiate under treatment, thereby escaping therapy. Dual targeting prevents selection and plasticity in SCLC. NE neuroendocrine, ROS reactive oxygen species, GSH glutathione, TRX thioredoxin. The scheme was drawn using fully licensed Biorender.com.