Oncogenic KRAS Promotes Ferroptosis in Pancreatic Cancer Through Regulation of the Fosl1-Tfrc Axis

Abstract Mutant KRAS activation occurs in most of pancreatic ductal adenocarcinoma (PDAC), which induce the sensitivity to ferroptosis of PDAC cells, but the underlying mechanism is still poorly understood. Here, we show how KRAS acts in signaling to activate transcription factor FOSL1, which promotes the expression of the iron uptake receptor TFRC. In PDAC cells, repression of TFRC by KRAS/FOSL1 signaling inhibited intracellular iron levels, thereby restricting the occurrence of ferroptosis. Furthermore, the KRAS/FOSL1/TFRC axis can make the PDAC cells vulnerable to alteration of the iron level in the tumor microenvironment. Our study highlights a pivotal mechanism of PDAC ferroptosis through iron metabolism and supports a new therapeutic strategy for PDAC with superior potential.