Major vault protein (MVP) is a scaffolding component of cytoplasmic vault structures involved in signal transduction and cellular protection mechanisms. MVP negatively regulates IFNG-mediated STAT1 signaling and SRC/MAP kinase pathways. In vascular endothelium, MVP promotes Parkin-mediated mitophagy by binding Parkin and preventing NEDD4L-mediated degradation, thereby reducing endothelial injury and limiting neointimal hyperplasia and atherosclerosis 1. In hepatocellular carcinoma (HCC), MVP functions as an oncogenic RNA-binding protein that suppresses ferroptosis through PGAM5-dependent post-translational modification, enabling it to stabilize LCN2 mRNA and reduce lipid peroxidation, promoting sorafenib resistance 2. MVP expression is elevated through histone lactylation in HCC, where it stabilizes PD-L1 protein by blocking β-TrCP-mediated degradation, driving immunotherapy resistance 3. Additionally, MVP supports mevalonate pathway flux and protein prenylation, contributing to cancer cell survival and immune evasion in pancreatic ductal adenocarcinoma 4. Pharmacological MVP inhibition with tenapanor or targeting the lactylation-MVP-PD-L1 axis represents promising therapeutic strategies to enhance ferroptosis, restore immunotherapy sensitivity, and overcome treatment resistance in multiple cancer types.