Mechanistically, VHL promotes the ubiquitination and degradation of HIF-2α, thus increasing the polyunsaturated fatty acids (PUFA), which are suppressed by HIF-2α, a lipid more susceptible to peroxidation, by activating the expression of hypoxia-inducible and lipid droplet-related protein (HILPDA) (Miess et al., 2018), finally contributing to ferroptosis in VHL-deficient ccRCC. Here, EPAS1 is linked to nonpapillary renal cell carcinoma.