Targeting HIF-2α in colorectal cancer reveals a cholesterol biosynthesis-dependent ferroptotic vulnerability.

[UNLABELLED] Colorectal carcinoma (CRC) remains a major cause of cancer-related mortality with rising incidence in individuals under 55, highlighting the need for novel therapeutic strategies. Hypoxia-inducible factor 2 alpha (HIF-2α) has been genetically validated as a critical driver of colorectal tumorigenesis, with intestinal epithelium–specific deletion in mice markedly reducing tumor formation. PT2385, a selective small-molecule HIF-2α inhibitor applied in renal cell carcinoma treatment, has not been evaluated in CRC. Here, we demonstrate that HIF-2α inhibition with PT2385 alone fails to suppress CRC growth in vitro under normoxic or hypoxic conditions and in xenograft models in vivo. To identify vulnerabilities induced by HIF-2α blockade, we performed an unbiased CRISPR metabolic screen. This revealed cholesterol biosynthesis as a critical dependency. Targeting this pathway with clinically approved statins (atorvastatin, pitavastatin, simvastatin) synergized with PT2385 to suppress CRC cell growth, reduce colony formation, and enhance cell death. Genetic knockdown of HIF-2α Mechanistic studies show that combined HIF-2α and HMG-CoA reductase inhibition with statins promotes ferroptosis, characterized by increased lipid peroxidation and depletion of antioxidant metabolites. These effects are fully reversed by the ferroptosis inhibitor liproxstatin-1. In vivo, co-administration of PT2385 and atorvastatin significantly reduced tumor growth and increased ferroptotic cell death in xenografts, confirming the mechanistic link. Collectively, these findings uncover a metabolic vulnerability of CRC to dual HIF-2α and cholesterol biosynthesis inhibition supporting a clinically actionable strategy that leverages safe, FDA-approved statins to potentiate HIF-2α-targeted therapy.

[SUPPLEMENTARY INFORMATION] The online version contains supplementary material available at 10.1186/s40170-026-00421-w.