Anti-cancer Activity of Conjugated Fatty Acids Mediated by Ferroptosis

Abstract

Conjugated fatty acids (CFAs) are known for their anti-tumor activity, yet their underlying mechanisms remain unclear. Here, we identify CFAs as inducers of glutathione peroxidase 4 (GPX4) degradation via chaperone-mediated autophagy (CMA). CFAs such as α-eleostearic acid (α-ESA) promoted GPX4 degradation, mitochondrial reactive oxygen species (ROS) generation, lipid peroxidation, and ultimately ferroptosis in cancer cell lines, including HT1080 and A549. These effects were suppressed by either genetic deletion of LAMP2A, an essential CMA component, or scavenging mitochondrial ROS. Oral administration of an α-ESA-rich oil suppressed xenograft tumor growth of wild-type, but not LAMP2A-deficient, HT1080 cells, concomitant with increased lipid peroxidation, GPX4 degradation, and cell death. Our findings identify mitochondria as the primary target of CFAs to induce lipid peroxidation and GPX4 degradation, offering insight into ferroptosis-based cancer therapy.

graphical abstract