Vhl, short for von Hippel-Lindau, is a crucial tumor suppressor gene. It is involved in the E3 ligase-mediated regulatory pathway, targeting hypoxia-inducible factor α (HIF1α and HIF2α) for proteasome degradation, thus playing a key role in oxygen sensing and the adaptive response to hypoxia [3,4,6,7]. Vhl is also associated with numerous HIF-independent pathways and is implicated in several vital cellular processes [4]. Genetic models, such as gene-deleted cell lines and KO mouse models, have been instrumental in studying its functions.

Loss-of-function of Vhl is a hallmark of clear cell renal cell carcinoma (ccRCC) [1]. In engineered Vhl-KO cell lines, these cells underwent epithelial-to-mesenchymal transition (EMT), showing increased motility but reduced proliferation and tumorigenicity compared to Vhl-expressing cells. In combined tumors with both Vhl + and Vhl-KO cells, rampant lung metastases occurred, indicating a cooperative metastatic mechanism [1]. In Vhl-KO murine kidney cancer models, the tumors had more immune cell infiltration. Tumor-associated macrophages from Vhl-deficient tumors showed enhanced glucose consumption, phagocytosis, and inflammatory transcriptional signatures, while lymphocytes had reduced activation and lower response to anti-PD-1 therapy [2]. Vhl-deficiency in renal cells led to reductive stress, characterized by an increased NADH/NAD+ ratio, impaired cellular respiration, and upregulated reductive carboxylation of glutamine [5].

In conclusion, Vhl is essential for regulating oxygen-sensing pathways and various cellular processes. The use of Vhl KO models has provided valuable insights into its role in ccRCC, including metastasis, immune landscape reprogramming, and metabolic changes. Understanding Vhl's functions through these models can potentially lead to new strategies for treating ccRCC.