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Ferroptosis is a form of cell death that has been associated with different diseases. Here the authors describe an association of ferroptosis with COVID-19 pulmonary pathologies in both patient samples and hamster model and suggest that the dysregulation in iron and lipid metabolism could provide targets to reduce pathology.

The tumour suppressor p53 controls non-apoptotic cell death (NACD) pathways, including ferroptosis, necroptosis and pyroptosis. This Review discusses the roles, mechanisms and physiological settings in which NACDs are regulated by p53, and their potential targeting for the treatment of human diseases.

Ferroptosis is a lipid-peroxide-driven cell death with promising therapeutic applications. Although peroxidation of various subcellular membranes can initiate ferroptosis, the authors found that the endoplasmic reticulum is an essential site.

Hepatic stellate cells regulate hepatocyte functions via R-spondin 3.

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.

In this Opinion article, the authors discuss how the induction of regulated cell death and inflammatory pathways may lead to an auto-amplification loop that causes tissue damage and organ failure. They propose that targeting both processes could be useful for treating a broad range of clinical conditions with an inflammatory basis.

Neuronal development is tightly controlled by nutrients and antioxidants. Here, authors show that ferroptosis, a cell death modality driven by lipid peroxidation, is required to be suppressed by vitamin A or antioxidants to ensure proper neuronal development.

Due to the limited efficacy of vaccines against SARS-CoV-2 and resistance to current therapies additional anti-viral therapeutics with pan-coronavirus activity are of high interest. Here, the authors screened 2.8 billion compounds from a DNA-encoded chemical library and identified small molecules that are non-covalent inhibitors targeting the conserved 3CL protease of SARS-CoV-2 and other coronaviruses.

Testing the relative fitness of thousands of yeast strains helps determine pathways and proteins targeted by small-molecule drugs

The discovery of a mechanism that guards against a type of cell death called ferroptosis reveals a system that regenerates a ubiquitous protective component of biological membranes, and might offer a target for anticancer drugs.

In this Review, Dai, Stockwell, Kroemer, Tang and colleagues offer a comprehensive discussion of the molecular regulation of ferroptosis and highlight how this may be potentially leveraged for therapeutic benefit for disease treatment.

Diet intervention is emerging as an option to improve cancer therapy. Here, the authors show that a diet with restrictive cysteine and methionine synergizes with a ferroptosis inducer to increase cell death and survival in glioma preclinical models.

GAS41 is recognized as a histone reader and oncogene, but the mechanism by which GAS41 contributes to tumorigenesis is not well understood. Here, the authors discover that GAS41 is a ferroptosis repressor that anchors NRF2 to chromatin, promoting tumor growth.

Small molecule drugs promise to remain a valuable tool in controlling the ongoing COVID-19 pandemic. Here the authors describe optimized drug-like small molecule inhibitors of the SARS-CoV-2 3CL protease for potential treatment of COVID-19.

p53 is able to induce ferroptosis in response to reactive oxygen species (ROS)-induced stress and suppresses tumour growth. Here, the authors show that iPLA2β suppresses p53-medated ferroptosis by cleaving and detoxifying peroxidized lipids and that this is independent of canonical ferroptosis regulator GPX4.

Biochemical and structural characterization of a homozygous point mutation in the GPX4 gene (R152H) reveals loss of enzymatic function and resistance to degradation. Therapeutic treatments such as selective antioxidants can overcome R152H defects.

The level of an individual protein in cells treated with combinations of drugs is best explained by simple linear superposition of the protein levels in response to single drugs. This finding may facilitate rational design of higher order drug combinations.

Chemical genetics is the study of gene-product function in a cellular or organismal context using exogenous ligands. In this approach, small molecules that bind directly to proteins are used to alter protein function, enabling a kinetic analysis of the in vivo consequences of these changes. Recent advances have strongly enhanced the power of exogenous ligands such that they can resemble genetic mutations in terms of their general applicability and target specificity. The growing sophistication of this approach raises the possibility of its application to any biological process.

The essential SARS-CoV-2 3CL protease is of interest as a drug target. Here, the authors identify three 3CL inhibitors and characterize them both in vitro and with a cell-based assay, and they also present the inhibitor-bound 3CL crystal structures, which may allow for the design of improved compounds.

Lee et al. show that energy stress inhibits ferroptosis through AMPK activation and demonstrate a role for AMPK in ferroptosis-associated renal ischaemia–reperfusion injury in vivo.

Expression of a Huntington's-disease variant of huntingtin protein causes accumulation of the chaperone protein disulfide isomerase. This protein is the target of compounds obtained from screening for those that can alleviate cell death promoted by the mutant huntingtin, and represents a new connection between protein misfolding and cell death.

Orienting cancer drug discovery to the patient requires relating the genetic features of tumors to acquired gene and pathway dependencies and identifying small-molecule therapeutics that target them.

Several forms of non-apoptotic cell death, such as necroptosis, pyroptosis, parthanatos and ferroptosis, are implicated in degenerative diseases, cancer and inflammation. This article describes the molecular pathways regulating these forms of cell death and gives an update on small-molecule inhibitors being developed to target these pathways.

FINO₂ is a small molecule that requires the endoperoxide moiety and hydroxyl group to promote ferroptosis through indirect inhibition of GPX4 enzymatic function and direct oxidation of iron, resulting in increased lipid peroxidation.

Embryonic stem cells have great potential in medicine, but the current methods used to grow them prevent their therapeutic use. A dual-action compound has been discovered that may help solve this problem.

Modulatory profiling of lethal small-molecule compounds identified FIN56 as an inducer of ferroptosis. FIN56 promotes the degradation of glutathione peroxidase 4 and directly activates squalene synthase, an enzyme involved in cholesterol synthesis.

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.

A small-molecule inhibitor of protein secretion has been found that targets Cdc42, a regulator of the secretory pathway. This compound acts through a previously undescribed mechanism—by recruiting a protein inhibitor.

A small-molecule activator of procaspase 3, 1541, forms chemical fibrils. shRNA screens, caspase proteomics and small-molecule profiling reveal that these fibrils enter cells through endocytosis and promote a distinctive form of cell death.

Ferroptosis is a form of regulated cell death driven by iron-dependent phospholipid peroxidation. Since its formal identification in 2012, multiple studies have addressed molecular mechanisms, regulation and functions of ferroptosis, associating this cell death modality with various pathologies, but also proposing its roles in normal physiology and potential for therapeutic targeting.

Arachidonyl and adrenoyl PE phospholipids generated by ACSL4, an acyl-CoA synthase, are doubly or triply oxidized by lipoxygenases and other iron-containing sources of oxidation to promote ferroptotic cell death.

Organ Mapping Antibody Panels are a community-led initiative to create standardized antibody panels for multiplexed spatial imaging.

The action mechanism of a RAS–RAF–MEK–pathway selective anti-tumour agent is described, this compound acts through mitochondrial voltage-dependent anion channels, a novel target for anti-cancer drugs.

Ferroptosis in cancer cells can be regulated by cadherin-mediated intercellular contacts, NF2–Hippo signalling, and activity of the YAP transcription co-activator.

Forms of cell death besides apoptosis and necrosis are becoming increasingly well understood, and are relevant to many disease contexts. Here, Conradet al. describe the mechanisms underlying regulated forms of necrosis — including necroptosis, ferroptosis, parthanatos and cyclophilin D-mediated necrosis — and efforts to induce or prevent them in disease.

Ferroptosis is a regulated form of non-apoptotic cell death implicated in pathological settings. To be exploited clinically, ferroptosis requires reagents that unequivocally detect ferroptosis in human and animal tissues. Such tools may enable development of ferroptosis-based medicines for diverse diseases.

Therapy-resistant cancer cell states identified across diverse contexts are selectively vulnerable to ferroptotic cell death induced by inhibition of lipid peroxidase pathways converging on GPX4.

The Human BioMolecular Atlas Program (HuBMAP) presents its production phase: the generation of spatial maps of functional tissue units across organs from diverse populations and the creation of tools and infrastructure to advance biomedical research.

Iron is essential for biological systems but can also damage or kill cells, leading to a variety of disease states. A review of mechanisms leading to Fe- and ROS-dependent cell death highlights the vast array of open questions in this complex field.