Vhl, the von Hippel-Lindau gene, is a crucial tumor suppressor. It functions as part of an E3 ligase complex targeting hypoxia-inducible factor α (HIFα, including HIF1α and HIF2α) for proteasome degradation in the oxygen-sensing pathway. This pathway is vital for cells to adapt to hypoxia. Germline Vhl mutations cause von Hippel-Lindau disease, and somatic inactivation drives clear cell renal cell carcinoma (ccRCC) [3,4,6,7]. Genetic models, like gene-deleted cell lines and KO mouse models, are valuable for studying Vhl's function.

In four RCC models with Vhl gene deletion (Vhl-KO), cells underwent epithelial-to-mesenchymal transition (EMT), showing increased motility but reduced proliferation and tumorigenicity compared to Vhl-expressing cells. Combined tumors of Vhl + and Vhl-KO cells had rampant lung metastases, suggesting a cooperative metastatic mechanism [1]. In Vhl-KO murine kidney cancer Renca models, tumors had more immune cell infiltration. Tumor-associated macrophages from Vhl-deficient tumors had enhanced glucose consumption, phagocytosis, and inflammatory transcriptional signatures, while lymphocytes showed 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 other metabolic changes [5].

In conclusion, Vhl plays a fundamental role in oxygen sensing, cell metabolism, and tumor suppression. Through gene-knockout models, we've learned its significance in ccRCC metastasis, immune landscape reprogramming in renal tumorigenesis, and metabolic regulation in renal cells. These findings contribute to understanding the pathogenesis of related diseases and may guide the development of new therapeutic strategies.