VHL is a tumor suppressor that functions as a target recruitment subunit of an E3 ubiquitin ligase complex 12. Under normoxic conditions, VHL recognizes hydroxylated hypoxia-inducible factor (HIF) alpha subunits and targets them for proteasomal degradation, thereby suppressing HIF-dependent transcription of pro-angiogenic genes like VEGF 34. This oxygen-sensing mechanism is critical for preventing excessive vascularization. Additionally, VHL negatively regulates mTORC1 signaling by promoting RPTOR degradation 5. Recently discovered non-canonical roles include mitochondrial VHL's inhibition of leucine catabolism under hypoxia, rewiring cellular metabolism to support survival 6. Lactate-induced lactylation of HIF-1α can override VHL-mediated degradation, revealing metabolic control of hypoxic signaling 7. Germline VHL mutations cause von Hippel-Lindau syndrome, characterized by multifocal hemangioblastomas, renal cell carcinomas, pheochromocytomas, and pancreatic tumors 84. VHL loss also promotes metastatic potential through paracrine effects, with VHL-knockout cells secreting periostin to enhance neighboring VHL-expressing cell motility 9. Understanding VHL's multifaceted roles in oxygen sensing and metabolism has enabled targeted therapeutic approaches for VHL disease and sporadic cancers.