ZNF395 Is a Hypoxia-Responsive Regulator of Mitochondrial Glutaminolysis in Clear Cell Renal Cell Carcinoma.

ABSTRACT: Hypoxia signaling induced by VHL deficiency fuels growth but also imposes metabolic stress on clear cell renal cell carcinomas (ccRCC). Many ccRCC cells depend on glutamine as the primary source of tricarboxylic acid (TCA) anaplerosis. Hypoxia-inducible factor α (HIFα) governs glycolysis but does not directly regulate glutamine metabolism; instead, the factor responsible for orchestrating glutamine metabolism and mitochondrial adaptations to hypoxia remains elusive. In this study, we showed that ZNF395 is a hypoxia-responsive factor that regulates glutamine metabolism in the mitochondria. When activated by a HIF2α-modulated superenhancer, ZNF395 facilitated the transcription of enzymes essential for glutaminolysis, including glutaminase (GLS) and isocitrate dehydrogenase 2. Functionally, Z

SUBMITTER: Koh J 

PROVIDER: S-EPMC12875648 | biostudies-literature | 2026 Feb

REPOSITORIES: biostudies-literature