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After performing a focused CRISPR–Cas9 screen, Skafar et al. identify riboflavin (vitamin B₂) as a regulator of FSP1 stability that modulates phospholipid peroxidation and ferroptosis sensitivity in cancer cells.

The ferroptosis suppressor protein FSP1 has a critical role in ferroptosis protection of tumours across multiple in vivo models and is linked to worse prognosis in human lung adenocarcinoma, suggesting its potential as a therapeutic target in lung cancer.

When 100 social and behavioural science claims were examined, 34% of reanalyses closely matched the original results, with 74% reaching the same conclusion, revealing limited robustness of single-path analyses and the need to address analytical uncertainty.

17β-oestradiol establishes an anti-ferroptotic state in female kidney tubules.

Targeting FSP1 in lymph nodes has considerable potential for blocking melanoma progression.

Tumour location dictates ferroptosis resistance. A study indicates that peritumoural adipose tissue aids tumours in evading ferroptosis by supplying tryptophan metabolites, including kynurenine and 3-hydroxykynurenine, which block NCOA4-mediated ferritinophagy to lower levels of labile iron and suppress lipid peroxidation.

Ferroptosis has been connected to liver disease through unclear mechanisms. Here, the authors identify the terminal enzyme of cholesterol synthesis, 7-dehydrocholesterol reductase, as a regulator of ferroptosis in hepatocytes that suppresses ferroptosis through 7-dehydrocholesterol accumulation.

Extensive mutational analyses of ferroptosis suppressor protein-1 (FSP1) reveal its molecular mechanism in ferroptosis prevention and uncover the mechanism of action of the FSP1 inhibitor iFSP1 and a new species-independent FSP1 inhibitor, viFSP1.

An inhibitor of the ferroptosis-suppressing FSP1 induces phase separation of FSP1, thereby impairing its function and reducing tumour growth.

Catalytic iron is associated with intensive care unit mortality and is known to cause free radical-mediated cellular toxicity. Here the authors show that a soluble ferrostatin-analogue (a ferroptosis inhibitor) protects mice from injury and death in experimental iron overload induced and genetic models of organ dysfunction, but not sepsis-induced multiorgan dysfunction.

Ferroptosis is a form of non-apoptotic cell death with unclear physiological relevance. Conrad and colleagues now report that unrestrained ferroptosis can lead to renal failure. They also identify a small molecule that limits ferroptosis in vivo.

ACSL4 is critical for induction of ferroptosis, a programmed form of necrotic cell death, through the production of long polyunsaturated fatty acids that can be inhibited in an in vivo ferroptosis model with a small molecule ACSL4 inhibitor.

Analyses of 2,658 whole genomes across 38 types of cancer identify the contribution of non-coding point mutations and structural variants to driving cancer.

Whole-genome sequencing data from more than 2,500 cancers of 38 tumour types reveal 16 signatures that can be used to classify somatic structural variants, highlighting the diversity of genomic rearrangements in cancer.

The flagship paper of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium describes the generation of the integrative analyses of 2,658 cancer whole genomes and their matching normal tissues across 38 tumour types, the structures for international data sharing and standardized analyses, and the main scientific findings from across the consortium studies.

Genetic factors have been found to be associated with severe COVID-19. Here, the authors integrated genomic, proteomic, and single-cell data to identify ELF5 as a candidate risk gene with a possible role in respiratory epithelial cells, which are targeted by SARS-CoV-2.

Although ferroptosis, an iron-dependent form of regulated cell death, is emerging as a therapeutic vulnerability in cancer, clinical translation is hindered by context-dependent regulation, a lack of predictive biomarkers and challenges in clinical trial design. In this Review, Wahida and Conrad examine the biological basis of ferroptosis, including its immunogenic potential, and outline the necessary steps towards translating ferroptosis-based therapies into the clinic.

Thioredoxin (Trx), Trx reductase, Txnip and NADPH together comprise the Trx system. Here the authors make a T cell-specific thioredoxin reductase-1 knockout mouse to show how this system reprograms cellular metabolism to enable T cell development, proliferation and responses.

Biochemical and lipidomic analyses identify an anti-ferroptotic function of vitamin K and reveal ferroptosis suppressor protein 1 (FSP1) as the enzyme mediating warfarin-resistant vitamin K reduction in the canonical vitamin K cycle.

Inhibition of the lipid peroxidase GPX4 promotes ferroptotic cell death. Here, the authors identify a complementary approach using conjugated linolenic fatty acids that trigger lipid peroxidation and ferroptosis via ACSL1, DGAT1/2, and neutral lipids.

The improper timing of transforming growth factor-β production is a hallmark of severe COVID-19 that may impede natural killer cell function and early control of infection.

In the absence of GPX4, FSP1 regenerates ubiquinol from the oxidized form, ubiquinone, using NAD(P)H and suppresses phospholipid peroxidation and ferroptosis in cells.

Some cancer cells exhibit high loads of reactive iron in lysosomes, and this feature is exploited by using fentomycin-1, a newly developed small molecule, to induce ferroptosis.

Chronic obstructive pulmonary disease is a progressive and incurable chronic condition that involves accumulation of inflammatory macrophages in the lung tissue. Authors here show in mouse models of lung disease that PRMT7, a protein arginine methyltransferase, is an important regulator of recruitment and the pro-inflammatory phenotype of macrophages.

Understanding deregulation of biological pathways in cancer can provide insight into disease etiology and potential therapies. Here, as part of the PanCancer Analysis of Whole Genomes (PCAWG) consortium, the authors present pathway and network analysis of 2583 whole cancer genomes from 27 tumour types.

There’s an emerging body of evidence to show how biological sex impacts cancer incidence, treatment and underlying biology. Here, using a large pan-cancer dataset, the authors further highlight how sex differences shape the cancer genome.

In somatic cells the mechanisms maintaining the chromosome ends are normally inactivated; however, cancer cells can re-activate these pathways to support continuous growth. Here, the authors characterize the telomeric landscapes across tumour types and identify genomic alterations associated with different telomere maintenance mechanisms.

With the generation of large pan-cancer whole-exome and whole-genome sequencing projects, a question remains about how comparable these datasets are. Here, using The Cancer Genome Atlas samples analysed as part of the Pan-Cancer Analysis of Whole Genomes project, the authors explore the concordance of mutations called by whole exome sequencing and whole genome sequencing techniques.

Integrative analyses of transcriptome and whole-genome sequencing data for 1,188 tumours across 27 types of cancer are used to provide a comprehensive catalogue of RNA-level alterations in cancer.

Viral pathogen load in cancer genomes is estimated through analysis of sequencing data from 2,656 tumors across 35 cancer types using multiple pathogen-detection pipelines, identifying viruses in 382 genomic and 68 transcriptome datasets.

Analysis of cancer genome sequencing data has enabled the discovery of driver mutations. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium the authors present DriverPower, a software package that identifies coding and non-coding driver mutations within cancer whole genomes via consideration of mutational burden and functional impact evidence.

A pan-cancer genomic analysis reports the effects of structural variations on chromatin domains (TADs). Most TAD disruptions do not result in appreciable changes in expression of nearby genes.

An analysis of 2,954 genomes from 38 cancer subtypes identified 19,166 retrotransposition events in 35% of samples. Aberrant LINE-1 retrotranspositions can lead to the deletion of tumor-suppressor genes as well as the amplification of oncogenes.

Whole-genome sequencing data for 2,778 cancer samples from 2,658 unique donors across 38 cancer types is used to reconstruct the evolutionary history of cancer, revealing that driver mutations can precede diagnosis by several years to decades.

Some cancer patients first present with metastases where the location of the primary is unidentified; these are difficult to treat. In this study, using machine learning, the authors develop a method to determine the tissue of origin of a cancer based on whole sequencing data.

The authors present SVclone, a computational method for inferring the cancer cell fraction of structural variants from whole-genome sequencing data.

Many tumours exhibit hypoxia (low oxygen) and hypoxic tumours often respond poorly to therapy. Here, the authors quantify hypoxia in 1188 tumours from 27 cancer types, showing elevated hypoxia links to increased mutational load, directing evolutionary trajectories.

Multi-omics datasets pose major challenges to data interpretation and hypothesis generation owing to their high-dimensional molecular profiles. Here, the authors develop ActivePathways method, which uses data fusion techniques for integrative pathway analysis of multi-omics data and candidate gene discovery.

The characterization of 4,645 whole-genome and 19,184 exome sequences, covering most types of cancer, identifies 81 single-base substitution, doublet-base substitution and small-insertion-and-deletion mutational signatures, providing a systematic overview of the mutational processes that contribute to cancer development.

In this study the authors consider the structural variants (SVs) present within cancer cases of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. They report hundreds of genes, including known cancer-associated genes for which the nearby presence of a SV breakpoint is associated with altered expression.

Cancers evolve as they progress under differing selective pressures. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, the authors present the method TrackSig the estimates evolutionary trajectories of somatic mutational processes from single bulk tumour data.

In 2012, a study revealed a unique form of cell death, termed ferroptosis, that is dependent on iron and unregulated lipid peroxidation. We revisit how this paper changed the trajectory of ferroptosis research from its origins to its current state.