Beyond hypoxia and ccRCC: the expanding universe of VHL novel targets and next-generation therapeutics

The von Hippel-Lindau (VHL) gene encodes the core substrate-recognition subunit of the Cullin2-RING E3 ubiquitin ligase complex, regulating cellular oxygen sensing and proteostasis. While targeting the canonical VHL-hypoxia-inducible factor (HIF) axis (e.g. belzutifan) has improved advanced clear cell renal cell carcinoma (ccRCC) management, intrinsic non-responsiveness and acquired resistance to HIF-2α inhibitors present major clinical limitations. Expanding beyond the HIF-centric paradigm reveals a broader network of non-canonical VHL targets, offering new opportunities for therapeutic development across ccRCC and pan-cancer contexts. This review provides an evidence-graded synthesis of novel VHL targets spanning epigenetic regulation (e.g. ZHX2, SETDB1, METTL3/METTL14), metabolic reprogramming (e.g. NDRG3, TFAM), extracellular matrix architecture (e.g. fibronectin, COL4A2), and immune modulation (e.g. TBK1). Supporting evidence across these targets ranges from direct biochemical ubiquitination to indirect downstream observations, derived predominantly from preclinical cell-line and xenograft models. Disruption of VHL and these non-HIF networks contributes to oncogenesis across diverse malignancies. Translating these mechanistic insights catalyzes two distinct therapeutic modalities. For VHL-deficient malignancies, selectively intercepting unshielded downstream effectors with small-molecule inhibitors provides rational, vulnerability-targeted salvage strategies. Conversely, in VHL-proficient malignancies, the exceptional chemical tractability of VHL has been repurposed by proteolysis targeting chimeras (PROTACs). VHL-recruiting PROTACs hijack operational ligase machinery to degrade targeted oncogenic drivers, including some previously "undruggable" oncogenes. These next-generation degraders offer potential biomarker-driven strategies to overcome current therapeutic bottlenecks in ccRCC and other associated malignancies. However, current evidence derives predominantly from in vitro and animal models. Realizing the clinical potential of VHL-targeted strategies requires addressing key unresolved questions regarding substrate directness, tissue tropism, and resistance trade-offs. Further investigating these core mechanistic and pharmacological bottlenecks will be essential to guide next-generation therapies in VHL-associated malignancies.