YAP/TEAD-activated TAG synthesis and peroxidation in lipid droplets confer ROS resistance in cancer stem cells

BACKGROUND: Cancer stem cells (CSCs) exhibit reduced levels of reactive oxygen species (ROS) despite increased oxidative phosphorylation, through mechanisms that remain poorly understood. Understanding these mechanisms could lead to new strategies for identifying and eradicating CSCs. METHODS: We combined lipidomic profiling, RNA-sequencing (RNA-seq), and TAGsig analysis to identify key lipids and genes involved in CSC-mediated resistance to ROS. These findings were further validated through a series of in vitro and in vivo experiments. RESULTS: YAP/TEAD pathway to activate transcription of TAG synthesis genes, enhancing resistance to ROS. CONCLUSION: We demonstrate that TAG in peri-mitochondrial LDs functions as a ROS scavenger, enabling CSCs to survive in hyperoxidative environments. Targeting the signaling pathways involved in TAG synthesis presents a potential strategy for eradicating CSCs.