Role of Oxysterol-Binding Protein Family in Cholesterol Metabolism and Cancer Progression: A Review

The oxysterol-binding protein-related proteins (ORPs) represent an evolutionarily conserved family of lipid-binding and transport proteins that serve as critical regulators of cellular lipid homeostasis, membrane trafficking, and signaling networks in eukaryotes. Accumulating evidence demonstrates that ORPs exert profound influence on oncogenic processes through their ability to modulate tumor cell proliferation, survival, and metastatic potential via distinct molecular mechanisms. Our review provides an integrated analysis of ORP family members, highlighting their structurally conserved oxysterol-binding domains and functionally divergent roles in cancer biology: (1) oncogenic ORPs (ORP2-5) that drive tumor progression through lipid metabolic reprogramming; (2) tumor-suppressive ORP8 that constrains malignant transformation; (3) immunomodulatory ORP9 involved in pancreatic cancer microenvironment regulation; and (4) ORP6/7 and ORP10/11 that govern cell motility and metabolic pathways respectively, with emerging but incompletely understood roles in neoplasia. Importantly, we discuss the translational relevance of ORP targeting, exemplified by the development of specific pharmacological inhibitors (Orpinolide and Ornithogalum saundersiae steroidal saponin-1) that disrupt oxysterol-binding protein/ORP4-mediated lipid transfer in cancer cells. By synthesizing current knowledge across solid tumors and hematologic malignancies, this work establishes a conceptual framework for understanding ORP-mediated oncogenesis and explores their potential as therapeutic targets in precision oncology approaches.