Andrew Darwin Laboratory website. Academic Microbiology research laboratory at NYU School of Medicine. New York, NY, USA.

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l-2-Hydroxyglutarate is identified as a legitimate physiological signalling metabolite, and control of its levels is essential for postnatal growth and survival and correct renal development and funct...

Researchers created a CRISPR-based tool to pinpoint genes the cancer turns off

Ferroptosis is a cell death mechanism characterized by the accumulation of iron-catalyzed lipid peroxides in membrane lipid acyl chains and subsequent loss of membrane integrity.1 Despite thorough investigation of its mechanisms in cultured cells, induction of ferroptosis has unresolved clinical utility in cancer therapy. Here, we systematically evaluate ferroptosis induction via multiple mechanisms, in both cell and tumor models, using focused genetic screens, genetic loss-of-function systems, and pharmacological perturbations. Through this analysis we identify cancer cell line subsets with distinct responses to canonical ferroptosis inducers and suppressors and define the underpinnings of each. Inhibition of central in vitro ferroptosis suppressors GPX4, GCLC, or SLC7A11 across these multiple models fails to impact established tumor growth. In contrast, deficiency in the cytosolic thioredoxin reductase and pharmacologic GCLC inhibition potently induces tumor regression and triggers a form of non-ferroptotic cell death regulated by cystine availability and translation. These analyses further reveal that the principal essential function of environmental cystine in cultured cells is to support selenoprotein function, identified through investigating our finding that beta-mercaptoethanol supports exponential growth in cystine-free conditions. Thus, while ferroptosis activation may be efficacious alone or in combination with other therapies in specific tumor contexts, cell culture systems greatly overestimate the potential anti-cancer effects of ferroptosis induction via the GPX4 axis. ### Competing Interest Statement The authors have declared no competing interest. NIH Common Fund, R01CA286141, R01GM132491, P30CA016087

The request comes amid continuing uncertainty over federal funding, with research and thousands of jobs on the line.

A forward genetic screen in Caenorhabditis elegans reveals that decreased levels of the ferredoxin FDX2 suppress the loss of frataxin in worms and in mice by relief of FDX2 inhibition of fra...

Nature Genetics - Analysis of 14,106 tumor genomes highlights recurrent mutations in mitochondrial ribosomal RNA encoded within the mitochondrial genome. Mutations occur at hotspot positions and...

Khan et al. apply machine learning to identify substrates of UNC93A, SLC45A4, and SLC25A45. Biochemical assays and in vivo metabolite tracing establish SLC25A45 as a key mediator of mitochondrial impo...

During nutrient deprivation, activation of the protein kinase GCN2 regulates cell survival and metabolic homeostasis. In addition to amino acid stress, GCN2 is activated by a variety of cellular stres...

Nature - Basal cells, rather than neuroendocrine cells, have been identified as the probable origin of small cell lung cancer and other neuroendocrine–tuft cancers, explaining...

The cortex fuels essential physiological processes with glucose-derived carbon, while gliomas fuel their aggressiveness by rerouting glucose carbon pathways and scavenging alternative carbon sources s...

Chen et al. show that PEX39 cooperates with PEX7 in the peroxisomal import of proteins containing a PTS2 site and uncover an (R/K)PWE motif in PEX39 and PEX13 that binds to PEX7 and facilitates the im...

APC/C activity is transiently inhibited to generate a pulse of glycolysis that is required for mammalian cell cycle entry.

Rao and Cai et al. perform a detailed metabolic comparison between primary tumours from patients and their matching xenografts, which identify conserved as well as divergent metabolic patterns.

In 2019, scientists discovered Jo Cameron, a Scottish woman with a rare genetic mutation that prevents her from feeling pain, anxiety, or fear and allows her to heal without scarring. This condition...

NYU Langone researchers have helped an 8-year-old boy regain mobility using an experimental treatment.