HDLBP (high-density lipoprotein binding protein) is a 110-kDa RNA-binding protein belonging to the evolutionarily conserved vigilin family, characterized by 14-15 KH domains 1. Localized primarily at the cytoplasmic face of the endoplasmic reticulum, with additional nuclear and cytosolic distribution 1, HDLBP serves multiple cellular functions. Its primary role involves protecting cells from cholesterol overaccumulation and facilitating cholesterol transport 2. Mechanistically, HDLBP binds and stabilizes ER-targeted mRNAs through multivalent CU-rich motif interactions in coding sequences, promoting translation efficiency of transmembrane and secreted proteins 3. Beyond lipid metabolism, HDLBP functions in translation regulation, chromosome 2, and viral infection responses 1. In disease contexts, HDLBP is significantly elevated in hepatocellular carcinoma (HCC) and lung adenocarcinoma, promoting malignant progression through multiple mechanisms: stabilizing lncFAL to suppress ferroptosis 4, stabilizing BRAF to enhance epithelial-mesenchymal transition 2, stabilizing RAF1 to maintain MAPK signaling and sorafenib resistance 5, and stabilizing GJB2 mRNA to promote glycolysis and CD8+ T cell exhaustion 6. Clinically, HDLBP expression correlates with HCC metastasis and represents a promising biomarker and therapeutic target.