Focus on cell death

Man and Kanneganti discuss how pattern-recognition sensors in innate immune cells recognize and respond to cell-death signatures, and highlight molecular targets for potential therapeutic development.

Gasdermins are a family of proteins that form membrane pores and elicit pyroptosis. This Review discusses recent work highlighting their regulation and emerging biological roles, including in non-lethal pore formation and host defence.

Several processes of regulated cell death engage or use mitochondria, which are thus central hubs that not only coordinate cell death but also elicit non-lethal signalling mediated by mitochondrial outer membrane permeabilization.

Ferroptosis is a form of cell death that is characterized by morphological abnormalities of mitochondria and the overwhelming peroxidation of phospholipids. Certain tumours are susceptible to ferroptosis, which could be exploited to treat cancers.

In this Perspective, Zhang discusses the latest advances in understanding of iron function, regulation and metabolism, as well as the implications for ferroptosis in health and disease.

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.

Cell death is an important biological process whose experimental detection and measurement can be difficult, especially when examining many conditions in parallel. The interpretation of cell death data is complicated by the diversity of measurement techniques and lack of standardized methods in the field. Here, we offer tips to help interpret cell death experiments.

This issue presents a Focus of specially commissioned articles that discuss cell death in its multiple forms, implications for homeostatic physiology and disease and outstanding questions in this expanding field.

Schwab, Rao et al. report that Zeb1 mediates enhanced ferroptosis sensitivity in cancer cells after EMT activation, associated with altered expression of selected lipogenic enzymes and an subsequent increase in the PUFA:MUFA ratio.

Zhou, Jiang, Dai et al report that upon ultraviolet-C radiation, full-length GSDME can induce pyroptosis without cleavage, likely due to conformational change and oxidative oligomerization after increased PARylation and mitochondrial lipid ROS levels.

Davidson et al. visualize ferroptosis-like cell death using three-colour live imaging in vivo and demonstrate its role in triggering macrophage recruitment but delaying resolution of inflammation during wounding in the Drosophila embryo.

Morgan, Pernes and colleagues perform mass spectrometry-based targeted lipidomics and provide a comprehensive lipid profile of human and mouse immune cells, which they then show confer differential ferroptosis susceptibilities.

Yang, Zhang et al. identify a non-canonical form of necroptosis driven by nuclear RIPK1-mediated nuclear membrane rupture as a result of ZMPSTE24 deficiency and defective prelamin A processing commonly observed in progeroid disorders.

Xu and colleagues identify a sequential palmitoylation–depalmitoylation mechanism that controls GSDMD cleavage by caspases, plasma membrane trafficking and oligomerization, thereby triggering pyroptosis in a spatial and temporal manner.

Zhu et al. show that loss of WIPI4, as seen in β-propeller protein-associated neurodegeneration, causes ferroptosis independently of autophagy due to an imbalance in phosphatidylethanolamine levels.

Cui, Guo, Liu et al. identify a bacterial species, Peptostreptococcus anaerobius, in the gut that produces a tryptophan metabolite and engages intracellular pathways to modulate ferroptosis-suppressor protein 1 activity, thereby suppressing ferroptosis and promoting colorectal cancer development.

Kumari et al. show that host-derived extracellular vesicles capture systemic LPS and transfer it to the cytosol of immune cells via CD14-dependent endocytosis, triggering caspase-11-mediated gasdermin D activation and pyroptosis.

Zhang, Xu, Liu, Wang et al. identify an inhibitory mechanism for RIPK1 kinase through EGLN1/pVHL-mediated proline hydroxylation, which is disrupted upon prolonged hypoxia that activates RIPK1 activity to promote cell death and inflammation.

Yang, Zhao, Wang and colleagues identify and characterize a pyrimidine biosynthetic complex pyrimidinosome that is regulated by AMP-activated protein kinase and facilitates dihydroorotate dehydrogenase-mediated ferroptosis resistance, thereby regulating cancer cell proliferation and survival.

Wu et al. show that, upon activation by insulin-like growth factor 1 receptor and AKT, creatine kinase B exhibits a moonlighting function as protein kinase to phosphorylate glutathione peroxidase 4 to prevent its degradation, thereby suppressing ferroptosis and enhancing tumour growth in mice.

Liu, Nie et al. identify disulfidptosis as a form of cell death resulting from aberrant accumulation of disulfide bonds in actin cytoskeleton proteins that is induced following glucose starvation and dependent on SLC7A11-mediated cystine uptake.

Deshwal et al. show that the protease PARL regulates coenzyme Q (CoQ) via the lipid transfer protein STARD7. Mitochondrial STARD7 ensures CoQ synthesis; cytosolic STARD7 preserves CoQ transport to the membrane, protecting cells against ferroptosis.

Lee et al. uncover a previously uncharacterized role of OASL in virus-induced necroptosis. OASL chaperones the assembly of RIPK3 and ZBP1 via liquid-liquid phase separation, which induces RIPK3 and necroptosis activation, thereby modulating inflammation and host defence against viral infection.

Nguyen et al. show that the E3 ubiquitin ligase MARCHF6 acts as an NADPH sensor to suppress ferroptosis. Mechanistically, NADPH binds to MARCHF6 and activates its E3 ligase activity, enhancing the degradation of pro-ferroptosis proteins.

Chen et al. examine the cellular necrosome using STORM and uncover the rod-shaped structure formed by mosaics of RIP1 and RIP3 oligomers.

Through CRISPR–Cas9 and kinase inhibitor screening, Zhang et al. show that PKCβII phosphorylates and activates ACSL4 to enhance polyunsaturated fatty acid-containing lipid biosynthesis, thereby promoting accumulation of lipid peroxidation and ferroptosis.

Ferroptosis is mediated by toxic accumulation of lipid peroxides. A new study reports that the transcription factor ZEB1 drives ferroptosis sensitivity by regulating the synthesis of highly oxidizable poly-unsaturated fatty acids. This creates a selective vulnerability that can be exploited to eliminate aggressive mesenchymal cancer cells.

Gasdermins (GSDMs) are mediators of cell death that trigger membrane lysis. A study shows that full-length GSDME induces pyroptosis after ultraviolet irradiation, involving GSDME PARylation that releases autoinhibition and lipid reactive oxygen species that promote pore formation. This study adds insights on how GSDMs can be activated non-canonically.

Diverse, specialized immune cells defend against pathogens and cancer cells. A new study reveals the comprehensive lipid compositions of these cells, with unique lipidomes associated with various immune cell types. They show that cell-specific lipid compositions determine a key functional phenotype: their susceptibility to ferroptosis.

Progeria, or premature ageing, is a devastating condition caused by defects in the nuclear envelope and is associated with systemic inflammation. A study now shows in animal models that inhibiting necroptosis, and particularly activity of the RIPK1 kinase, reduces inflammation and results in a meaningful extension in lifespan¹.

β-propeller protein-associated neurodegeneration (BPAN) is caused by loss of functional WIPI4. A new study reports that depletion of WIPI4 induces ferroptosis via changes in mitochondrial membrane lipids, independently of the role of WIPI4 in autophagy, providing insights into the cause of neurodegeneration in BPAN.

Different gut microbial metabolites have the potential to promote and protect against colorectal cancer (CRC). A study now links trans-3-indoleacrylic acid (IDA), a metabolite derived from Peptostreptococcus anaerobius, with colorectal carcinogenesis through a distinct ferroptosis pathway AHR–ALDH1A3–FSP1–CoQ₁₀.

The PHD–pVHL pathway is essential for oxygen-dependent prolyl hydroxylation of HIFA. A recent study identifies RIPK1 as a hydroxylation target in this pathway during hypoxia-induced cell death and presents a 2.8 Å resolution crystal structure of the pVHL–elongin B/C complex bound to hydroxylated RIPK1.

A new study shows that the enzymes involved in de novo pyrimidine synthesis and ferroptosis form a complex called the pyrimidinosome, which is controlled by AMPK. Cancer cells low in AMPK expression rely on the pyrimidinosome, suggesting that co-inhibition of AMPK and the pyrimidinosome represents a potential cancer treatment strategy.

The selenoprotein glutathione peroxidase 4 (GPX4) is the guardian of ferroptosis, a form of cell death earmarked by unrestrained lipid peroxidation. A new study shows that the metabolic enzyme creatinine kinase B (CKB) phosphorylates GPX4, which may influence the susceptibility of cancer cells to ferroptosis.

Programmed cell death (PCD) enables cells to co-ordinate their exit to benefit the surviving organism. A new study describes how cells can programme their death by inducing extensive disulfide bonding of the actin cytoskeleton in response to an imbalance of cystine, a raw material for glutathione production.

Extramitochondrial coenzyme Q (CoQ) can function as a potent anti-ferroptosis radical trapper. However, it is largely unknown how CoQ is transported from mitochondria to the plasma membrane. A study now suggests that PARL-mediated STARD7 processing is responsible for the cellular distribution of CoQ.

NADPH levels serve as a biomarker of sensitivity to ferroptosis, but the regulators that detect cellular NADPH levels and modulate downstream ferroptosis responses are unknown. A study now identifies MARCHF6 in the ubiquitin system as an NADPH sensor that suppresses ferroptosis.

Necrosomes formed by RIPK1–RIPK3 mediate necroptosis. Super-resolution microscopy identifies the architectural features of necrosomes and provides mechanistic insights into the signalling from RIPK1 to RIPK3 when RIPK1 is activated to mediate necroptosis, and from RIPK3 to RIPK1 when RIPK3 is inhibited to mediate apoptosis.

Lipid metabolism is crucial for the execution of ferroptosis. A new study demonstrates that the function of the lipid metabolic enzyme ACSL4 is positively regulated by phosphorylation, leading to amplification of ferroptotic cell death. These results shed new light on the regulation of ferroptosis execution in cancer cells.