KRAS Inhibitor Resistance Confers a Targetable Vulnerability to Ferroptosis in Pancreatic Ductal Adenocarcinoma

KRAS inhibitors represent a promising therapeutic frontier in pancreatic ductal adenocarcinoma (PDAC) treatment. However, the clinical benefit of KRAS inhibitors in PDAC is limited by the frequent emergence of resistance. Here, we demonstrated that acquisition of resistance to KRAS inhibitors rendered PDAC cells hypersensitive to ferroptosis. Untargeted lipidomic profiling revealed that resistant cells underwent extensive lipid metabolic reprogramming characterized by selective enrichment of polyunsaturated fatty acid-containing phosphatidylcholines (PC-PUFAs) and a concomitant reduction in monounsaturated fatty acid-containing species (PC-MUFAs). The orphan nuclear receptor NR2F2 was a critical determinant of ferroptosis sensitivity in resistant cells. NR2F2 expression was markedly elevated upon acquisition of resistance, accompanied by substantial changes in its occupancy at regulatory elements of key lipid metabolic genes. By altering chromatin accessibility, NR2F2 drove PUFA biosynthesis and phospholipid remodeling, creating a ferroptosis-prone lipid state. Collectively, these findings establish NR2F2-driven lipid metabolic rewiring as an intrinsic ferroptosis liability in KRAS inhibitor-resistant PDAC and reveal ferroptosis induction as a therapeutic strategy to overcome resistance to KRAS-targeted therapies.