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Clear-cell carcinomas (CCCs) are a histological group of highly aggressive malignancies commonly originating in the kidney and ovary. CCCs are distinguished by aberrant lipid and glycogen accumulation and are refractory to a broad range of anti-cancer therapies. Here we identify an intrinsic vulnerability to ferroptosis associated with the unique metabolic state in CCCs. This vulnerability transcends lineage and genetic landscape, and can be exploited by inhibiting glutathione peroxidase 4 (GPX4) with small-molecules. Using CRISPR screening and lipidomic profiling, we identify the hypoxia-inducible factor (HIF) pathway as a driver of this vulnerability. In renal CCCs, HIF-2α selectively enriches polyunsaturated lipids, the rate-limiting substrates for lipid peroxidation, by activating the expression of hypoxia-inducible, lipid droplet-associated protein (HILPDA). Our study suggests targeting GPX4 as a therapeutic opportunity in CCCs, and highlights that therapeutic approaches can be identified on the basis of cell states manifested by morphological and metabolic features in hard-to-treat cancers., Clear-cell carcinomas are aggressive tumours characterised by high accumulation of lipids and glycogen. Here, the authors report that these cancers have a common vulnerability to GPX4 inhibition-induced ferroptosis and using CRISPR screen and lipodomic profiling, they identify HIF-2α- HILPDA axis promotes ferroptosis via enrichment of PUFA lipids.

The study of rare variants may enhance our understanding of the genetic determinants of the metabolome. Here, we analyze the association between 217 plasma metabolites and exome variants on the Illumina HumanExome Beadchip in 2,076 participants in the Framingham Heart Study, with replication in 1,528 participants of the Atherosclerosis Risk in Communities Study. We identify an association between GMPS and xanthosine using single variant analysis and associations between HAL and histidine, PAH and phenylalanine, and UPB1 and ureidopropionate using gene-based tests (P, Several GWAS have identified many common variants associated with blood metabolites. Here, the authors use an exome array to identify low frequency, potentially functional variants that impact human metabolism.

Nature Communications 6: Article number:6791 (2015); Published 13 April 2015; Updated 21 May 2015. In Fig. 1c,d of this Article, the y axis labels were inadvertently changed from ‘Log isocitrate’ to ‘Log aconitase’ during the production process. The correct version of Fig. 1 appears below.

Alterations in metabolism influence lifespan in experimental models, but data in humans are lacking. Here we use liquid chromatography/mass spectrometry to quantify 217 plasma metabolites and examine their relation to longevity in a large cohort of men and women. In 647 individuals followed for up to 20 years, higher concentrations of the citric acid cycle intermediate, isocitrate, and the bile acid, taurocholate, are associated with lower odds of longevity, defined as attaining 80 years of age. In a larger cohort of 2,327 individuals with metabolite data available, higher concentrations of isocitrate but not taurocholate are also associated with worse cardiovascular health at baseline, as well as risk of future cardiovascular disease and death. None of the metabolites identified are associated with cancer risk. Our findings suggest that some, but not all, metabolic pathways to human longevity are dependent on modifying risk for the two most common causes of death.