MVP-LCN2 axis triggers evasion of ferroptosis to drive hepatocarcinogenesis and sorafenib resistance.

RNA-binding proteins (RBPs) are critical regulators in tumorigenesis and therapy resistance by modulating RNA metabolism. However, the role of RBPs in hepatocarcinogenesis and progression remains elusive. Here, RBPs screening and integrating analyses identify major vault protein (MVP) as an oncogenic RBP in the occurrence of hepatocellular carcinoma (HCC) and sorafenib resistance via suppressing ferroptosis. Mechanistically, reactive oxygen species (ROS) induces STAT3-mediated MVP transcription activation and high expression in HCC cells. Subsequently, phosphoglycerate mutase family member 5 (PGAM5) directly dephosphorylates MVP at S873, facilitating its binding to the mRNA of iron-sequestering cytokine LCN2 and maintains its stability, thereby attenuating ferroptosis by reducing lipid peroxidation and intracellular Fe content following sorafenib treatment. Notably, tenapanor, a potent pharmacological inhibitor of MVP, effectively disrupts the interaction between MVP and LCN2 mRNA and enhances ferroptosis and sorafenib sensitivity. Collectively, these findings underscore the central role of MVP in hepatocarcinogenesis and offer promising avenues to improve HCC treatment.