Ferroptosis promotes tumorigenesis in pancreatic cancer. GPX4, glutathione peroxidase 4; TMEM173, transmembrane protein 173. Schematic depicting the role of high-iron diets or GPX4 depletion in Kras-driven PDAC. The induction of ferroptosis by either high-iron diets or GPX4 depletion promotes oxidized nucleobase (e.g., 8-OHG) release and thus activates the TMEM173-dependent DNA sensor pathway, which finally results in macrophage infiltration and activation during Kras-driven PDAC. Consequently, macrophage depletion or pharmacological and genetic inhibition of the 8-OHG–TMEM173 pathway suppresses ferroptosis-mediated pancreatic tumorigenesis. The red line means the overexpression of GPX4 can inhibit the progression of ferroptosis.