Abstract
Cell death is critical for the development and homeostasis of almost all multicellular organisms. Moreover, its dysregulation leads to diverse disease states. Historically, apoptosis was thought to be the major regulated cell death pathway, whereas necrosis was considered to be an unregulated form of cell death. However, research in recent decades has uncovered several forms of regulated necrosis that are implicated in degenerative diseases, inflammatory conditions and cancer. The growing insight into these regulated, non-apoptotic cell death pathways has opened new avenues for therapeutic targeting. Here, we describe the regulatory pathways of necroptosis, pyroptosis, parthanatos, ferroptosis, cuproptosis, lysozincrosis and disulfidptosis. We discuss small-molecule inhibitors of the pathways and prospects for future drug discovery. Together, the complex mechanisms governing these pathways offer strategies to develop therapeutics that control non-apoptotic cell death.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Kerr, J. F., Wyllie, A. H. & Currie, A. R. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br. J. Cancer 26, 239–257 (1972).
Kist, M. & Vucic, D. Cell death pathways: intricate connections and disease implications. EMBO J. 40, e106700 (2021).
Galluzzi, L. et al. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ. 25, 486–541 (2018).
Tang, D., Kang, R., Berghe, T. V., Vandenabeele, P. & Kroemer, G. The molecular machinery of regulated cell death. Cell Res. 29, 347–364 (2019).
Shan, B., Pan, H., Najafov, A. & Yuan, J. Necroptosis in development and diseases. Genes Dev. 32, 327–340 (2018).
Dhuriya, Y. K. & Sharma, D. Necroptosis: a regulated inflammatory mode of cell death. J. Neuroinflammation 15, 199 (2018).
Degterev, A. et al. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat. Chem. Biol. 1, 112–119 (2005).
Degterev, A. et al. Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat. Chem. Biol. 4, 313–321 (2008).
Newton, K. Multitasking kinase RIPK1 regulates cell death and inflammation. Cold Spring Harb. Perspect. Biol. 12, a036368 (2020).
Bertrand, M. J. et al. cIAP1 and cIAP2 facilitate cancer cell survival by functioning as E3 ligases that promote RIP1 ubiquitination. Mol. Cell 30, 689–700 (2008).
Ofengeim, D. & Yuan, J. Regulation of RIP1 kinase signalling at the crossroads of inflammation and cell death. Nat. Rev. Mol. Cell Biol. 14, 727–736 (2013).
Legarda-Addison, D., Hase, H., O’Donnell, M. A. & Ting, A. T. NEMO/IKKγ regulates an early NF-κB-independent cell-death checkpoint during TNF signaling. Cell Death Differ. 16, 1279–1288 (2009).
Vincendeau, M. et al. Inhibition of canonical NF-κB signaling by a small molecule targeting NEMO-ubiquitin interaction. Sci. Rep. 6, 18934 (2016).
Micheau, O. & Tschopp, J. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell 114, 181–190 (2003).
Wang, L., Du, F. & Wang, X. TNF-α induces two distinct caspase-8 activation pathways. Cell 133, 693–703 (2008).
Hrdinka, M. et al. CYLD limits Lys63- and Met1-linked ubiquitin at receptor complexes to regulate innate immune signaling. Cell Rep. 14, 2846–2858 (2016).
Elliott, P. R. et al. SPATA2 links CYLD to LUBAC, activates CYLD, and controls LUBAC signaling. Mol. Cell 63, 990–1005 (2016).
Lork, M., Verhelst, K. & Beyaert, R. CYLD, A20 and OTULIN deubiquitinases in NF-κB signaling and cell death: so similar, yet so different. Cell Death Differ. 24, 1172–1183 (2017).
Keusekotten, K. et al. OTULIN antagonizes LUBAC signaling by specifically hydrolyzing Met1-linked polyubiquitin. Cell 153, 1312–1326 (2013).
Elliott, P. R. et al. Molecular basis and regulation of OTULIN-LUBAC interaction. Mol. Cell 54, 335–348 (2014).
Wertz, I. E. et al. De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-κB signalling. Nature 430, 694–699 (2004).
Cho, Y. S. et al. Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell 137, 1112–1123 (2009).
Li, J. et al. The RIP1/RIP3 necrosome forms a functional amyloid signaling complex required for programmed necrosis. Cell 150, 339–350 (2012).
Mompeán, M. et al. The structure of the necrosome RIPK1-RIPK3 core, a human hetero-amyloid signaling complex. Cell 173, 1244–1253.e10 (2018).
Sun, L. et al. Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell 148, 213–227 (2012).
Zhao, J. et al. Mixed lineage kinase domain-like is a key receptor interacting protein 3 downstream component of TNF-induced necrosis. Proc. Natl Acad. Sci. USA 109, 5322–5327 (2012).
Cai, Z. et al. Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis. Nat. Cell Biol. 16, 55–65 (2014).
Hildebrand, J. M. et al. Activation of the pseudokinase MLKL unleashes the four-helix bundle domain to induce membrane localization and necroptotic cell death. Proc. Natl Acad. Sci. USA 111, 15072–15077 (2014).
Kaiser, W. J. et al. Toll-like receptor 3-mediated necrosis via TRIF, RIP3, and MLKL. J. Biol. Chem. 288, 31268–31279 (2013).
Yang, S. H. et al. Nec-1 alleviates cognitive impairment with reduction of Aβ and tau abnormalities in APP/PS1 mice. EMBO Mol. Med. 9, 61–77 (2017).
Caccamo, A. et al. Necroptosis activation in Alzheimer’s disease. Nat. Neurosci. 20, 1236–1246 (2017).
Iannielli, A. et al. Pharmacological inhibition of necroptosis protects from dopaminergic neuronal cell death in Parkinson’s disease models. Cell Rep. 22, 2066–2079 (2018).
Ito, Y. et al. RIPK1 mediates axonal degeneration by promoting inflammation and necroptosis in ALS. Science 353, 603–608 (2016).
Ofengeim, D. et al. Activation of necroptosis in multiple sclerosis. Cell Rep. 10, 1836–1849 (2015).
Pan, L. et al. Activation of necroptosis in a rat model of acute respiratory distress syndrome induced by oleic acid. Sheng Li Xue Bao 68, 661–668 (2016).
Wang, L. et al. Receptor Interacting protein 3-mediated necroptosis promotes lipopolysaccharide-induced inflammation and acute respiratory distress syndrome in mice. PLoS One 11, e0155723 (2016).
Pan, L. et al. Necrostatin-1 protects against oleic acid-induced acute respiratory distress syndrome in rats. Biochem. Biophys. Res. Commun. 478, 1602–1608 (2016).
Mizumura, K. et al. Mitophagy-dependent necroptosis contributes to the pathogenesis of COPD. J. Clin. Invest. 124, 3987–4003 (2014).
Pouwels, S. D. et al. Cigarette smoke-induced necroptosis and DAMP release trigger neutrophilic airway inflammation in mice. Am. J. Physiol. Lung Cell Mol. Physiol. 310, L377–L386 (2016).
Luedde, M. et al. RIP3, a kinase promoting necroptotic cell death, mediates adverse remodelling after myocardial infarction. Cardiovasc. Res. 103, 206–216 (2014).
Smith, C. C. et al. Necrostatin: a potentially novel cardioprotective agent? Cardiovasc. Drugs Ther. 21, 227–233 (2007).
Oerlemans, M. I. et al. Inhibition of RIP1-dependent necrosis prevents adverse cardiac remodeling after myocardial ischemia-reperfusion in vivo. Basic Res. Cardiol. 107, 270 (2012).
Linkermann, A. et al. Rip1 (receptor-interacting protein kinase 1) mediates necroptosis and contributes to renal ischemia/reperfusion injury. Kidney Int. 81, 751–761 (2012).
Belavgeni, A., Meyer, C., Stumpf, J., Hugo, C. & Linkermann, A. Ferroptosis and necroptosis in the kidney. Cell Chem. Biol. 27, 448–462 (2020).
Duprez, L. et al. RIP kinase-dependent necrosis drives lethal systemic inflammatory response syndrome. Immunity 35, 908–918 (2011).
Zelic, M. et al. RIP kinase 1-dependent endothelial necroptosis underlies systemic inflammatory response syndrome. J. Clin. Invest. 128, 2064–2075 (2018).
Hou, J. et al. Discovery of potent necroptosis inhibitors targeting RIPK1 kinase activity for the treatment of inflammatory disorder and cancer metastasis. Cell Death Dis. 10, 493 (2019).
Kumari, S. et al. NF-κB inhibition in keratinocytes causes RIPK1-mediated necroptosis and skin inflammation. Life Sci. Alliance 4, e202000956 (2021).
Schünke, H., Göbel, U., Dikic, I. & Pasparakis, M. OTULIN inhibits RIPK1-mediated keratinocyte necroptosis to prevent skin inflammation in mice. Nat. Commun. 12, 5912 (2021).
Louhimo, J., Steer, M. L. & Perides, G. Necroptosis is an important severity determinant and potential therapeutic target in experimental severe pancreatitis. Cell Mol. Gastroenterol. Hepatol. 2, 519–535 (2016).
Günther, C. et al. Caspase-8 regulates TNF-α-induced epithelial necroptosis and terminal ileitis. Nature 477, 335–339 (2011).
Welz, P. S. et al. FADD prevents RIP3-mediated epithelial cell necrosis and chronic intestinal inflammation. Nature 477, 330–334 (2011).
Takahashi, N. et al. Necrostatin-1 analogues: critical issues on the specificity, activity and in vivo use in experimental disease models. Cell Death Dis. 3, e437 (2012).
Harris, P. A. et al. DNA-encoded library screening identifies benzo[b][1,4]oxazepin-4-ones as highly potent and monoselective receptor interacting protein 1 kinase inhibitors. J. Med. Chem. 59, 2163–2178 (2016).
Harris, P. A. et al. Discovery of a first-in-class receptor interacting protein 1 (RIP1) kinase specific clinical candidate (GSK2982772) for the treatment of inflammatory diseases. J. Med. Chem. 60, 1247–1261 (2017).
Wang, W. et al. RIP1 kinase drives macrophage-mediated adaptive immune tolerance in pancreatic cancer. Cancer Cell 34, 757–774.e7 (2018).
Mifflin, L., Ofengeim, D. & Yuan, J. Receptor-interacting protein kinase 1 (RIPK1) as a therapeutic target. Nat. Rev. Drug Discov. 19, 553–571 (2020).
Yoshikawa, M. et al. Discovery of 7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine derivatives as potent, orally available, and brain-penetrating receptor interacting protein 1 (RIP1) kinase inhibitors: analysis of structure-kinetic relationships.J. Med. Chem. 61, 2384–2409 (2018).
Patel, S. et al. RIP1 inhibition blocks inflammatory diseases but not tumor growth or metastases. Cell Death Differ. 27, 161–175 (2020).
Berger, S. B. et al. Characterization of GSK'963: a structurally distinct, potent and selective inhibitor of RIP1 kinase. Cell Death Discov. 1, 15009 (2015).
Delehouze, C. et al. 6E11, a highly selective inhibitor of receptor-interacting protein kinase 1, protects cells against cold hypoxia-reoxygenation injury. Sci. Rep. 7, 12931 (2017).
Najjar, M. et al. Structure guided design of potent and selective ponatinib-based hybrid inhibitors for RIPK1. Cell Rep. 10, 1850–1860 (2015).
Ren, Y. et al. Discovery of a highly potent, selective, and metabolically stable inhibitor of receptor-interacting protein 1 (RIP1) for the treatment of systemic inflammatory response syndrome. J. Med. Chem. 60, 972–986 (2017).
Mandal, P. et al. RIP3 induces apoptosis independent of pronecrotic kinase activity. Mol. Cell 56, 481–495 (2014).
Jiao, J., Wang, Y., Ren, P., Sun, S. & Wu, M. Necrosulfonamide ameliorates neurological impairment in spinal cord injury by improving antioxidative capacity. Front. Pharmacol. 10, 1538 (2019).
Shlomovitz, I. et al. Necroptosis directly induces the release of full-length biologically active IL-33 in vitro and in an inflammatory disease model. FEBS J. 286, 507–522 (2019).
Yan, B. et al. Discovery of a new class of highly potent necroptosis inhibitors targeting the mixed lineage kinase domain-like protein. Chem. Commun. 53, 3637–3640 (2017).
Frank, D. & Vince, J. E. Pyroptosis versus necroptosis: similarities, differences, and crosstalk. Cell Death Differ. 26, 99–114 (2019).
Martinon, F., Burns, K. & Tschopp, J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-β. Mol. Cell 10, 417–426 (2002).
Kayagaki, N. et al. Non-canonical inflammasome activation targets caspase-11. Nature 479, 117–121 (2011).
Yu, P. et al. Pyroptosis: mechanisms and diseases. Signal. Transduct. Target. Ther. 6, 128 (2021).
Xiao, L., Magupalli, V. G. & Wu, H. Cryo-EM structures of the active NLRP3 inflammasome disk.Nature 613, 595–600 (2023).
Broz, P. & Dixit, V. M. Inflammasomes: mechanism of assembly, regulation and signalling. Nat. Rev. Immunol. 16, 407–420 (2016).
Boucher, D. et al. Caspase-1 self-cleavage is an intrinsic mechanism to terminate inflammasome activity. J. Exp. Med. 215, 827–840 (2018).
Shi, J. et al. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature 526, 660–665 (2015).
Thornberry, N. A. et al. A novel heterodimeric cysteine protease is required for interleukin-1β processing in monocytes. Nature 356, 768–774 (1992).
Ghayur, T. et al. Caspase-1 processes IFN-γ-inducing factor and regulates LPS-induced IFN-γ production. Nature 386, 619–623 (1997).
Gu, Y. et al. Activation of interferon-γ inducing factor mediated by interleukin-1β converting enzyme. Science 275, 206–209 (1997).
Ding, J. et al. Pore-forming activity and structural autoinhibition of the gasdermin family. Nature 535, 111–116 (2016).
Liu, X. et al. Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature 535, 153–158 (2016).
Evavold, C. L. et al. The pore-forming protein gasdermin D regulates interleukin-1 secretion from living macrophages. Immunity 48, 35–44.e36 (2018).
Shi, J. et al. Inflammatory caspases are innate immune receptors for intracellular LPS. Nature 514, 187–192 (2014).
Palacios-Macapagal, D. et al. Cutting edge: eosinophils undergo caspase-1-mediated pyroptosis in response to necrotic liver cells. J. Immunol. 199, 847–853 (2017).
Duewell, P. et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464, 1357–1361 (2010).
Zhang, Y. et al. Coronary endothelial dysfunction induced by nucleotide oligomerization domain-like receptor protein with pyrin domain containing 3 inflammasome activation during hypercholesterolemia: beyond inflammation. Antioxid. Redox Signal. 22, 1084–1096 (2015).
Yin, Y. et al. Early hyperlipidemia promotes endothelial activation via a caspase-1-sirtuin 1 pathway. Arterioscler. Thromb. Vasc. Biol. 35, 804–816 (2015).
Heneka, M. T. et al. NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature 493, 674–678 (2013).
Venegas, C. et al. Microglia-derived ASC specks cross-seed amyloid-β in Alzheimer’s disease. Nature 552, 355–361 (2017).
Friker, L. L. et al. β-Amyloid clustering around ASC fibrils boosts its toxicity in microglia. Cell Rep. 30, 3743–3754.e6 (2020).
Doitsh, G. et al. Cell death by pyroptosis drives CD4 T-cell depletion in HIV-1 infection. Nature 505, 509–514 (2014).
Maltez, V. I. et al. Inflammasomes coordinate pyroptosis and natural killer cell cytotoxicity to clear infection by a ubiquitous environmental bacterium. Immunity 43, 987–997 (2015).
Loher, F. et al. The interleukin-1β-converting enzyme inhibitor pralnacasan reduces dextran sulfate sodium-induced murine colitis and T helper 1 T-cell activation. J. Pharmacol. Exp. Ther. 308, 583–590 (2004).
Boxer, M. B. et al. A highly potent and selective caspase 1 inhibitor that utilizes a key 3-cyanopropanoic acid moiety. ChemMedChem 5, 730–738 (2010).
Wannamaker, W. et al. (S)-1-((S)-2-{[1-(4-Amino-3-chloro-phenyl)-methanoyl]-amino}-3,3-dimethyl-butanoyl)-pyrrolidine-2-carboxylic acid ((2R,3S)-2-ethoxy-5-oxo-tetrahydro-furan-3-yl)-amide (VX-765), an orally available selective interleukin (IL)-converting enzyme/caspase-1 inhibitor, exhibits potent anti-inflammatory activities by inhibiting the release of IL-1β and IL-18.J. Pharmacol. Exp. Ther. 321, 509–516 (2007).
Flores, J. et al. Caspase-1 inhibition alleviates cognitive impairment and neuropathology in an Alzheimer’s disease mouse model. Nat. Commun. 9, 3916 (2018).
Coll, R. C. et al. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat. Med. 21, 248–255 (2015).
Coll, R. C. et al. MCC950 directly targets the NLRP3 ATP-hydrolysis motif for inflammasome inhibition. Nat. Chem. Biol. 15, 556–559 (2019).
Jiang, H. et al. Identification of a selective and direct NLRP3 inhibitor to treat inflammatory disorders. J. Exp. Med. 214, 3219–3238 (2017).
Marchetti, C. et al. OLT1177, a β-sulfonyl nitrile compound, safe in humans, inhibits the NLRP3 inflammasome and reverses the metabolic cost of inflammation. Proc. Natl Acad. Sci. USA 115, E1530–E1539 (2018).
Fatokun, A. A., Dawson, V. L. & Dawson, T. M. Parthanatos: mitochondrial-linked mechanisms and therapeutic opportunities. Br. J. Pharmacol. 171, 2000–2016 (2014).
Yu, S. W. et al. Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor. Science 297, 259–263 (2002).
Andrabi, S. A. et al. Poly(ADP-ribose) (PAR) polymer is a death signal. Proc. Natl Acad. Sci. USA 103, 18308–18313 (2006).
Yu, S. W. et al. Apoptosis-inducing factor mediates poly(ADP-ribose) (PAR) polymer-induced cell death. Proc. Natl Acad. Sci. USA 103, 18314–18319 (2006).
Kang, H. C. et al. Iduna is a poly(ADP-ribose) (PAR)-dependent E3 ubiquitin ligase that regulates DNA damage. Proc. Natl Acad. Sci. USA 108, 14103–14108 (2011).
Gatti, M., Imhof, R., Huang, Q., Baudis, M. & Altmeyer, M. The ubiquitin ligase TRIP12 limits PARP1 trapping and constrains PARP inhibitor efficiency. Cell Rep. 32, 107985 (2020).
Wang, Y. et al. Poly(ADP-ribose) (PAR) binding to apoptosis-inducing factor is critical for PAR polymerase-1-dependent cell death (parthanatos). Sci. Signal. 4, ra20 (2011).
Wang, Y. et al. A nuclease that mediates cell death induced by DNA damage and poly(ADP-ribose) polymerase-1. Science 354, aad6872 (2016).
Curtin, N. J. & Szabo, C. Poly(ADP-ribose) polymerase inhibition: past, present and future. Nat. Rev. Drug Discov. 19, 711–736 (2020).
Kam, T. I. et al. Poly(ADP-ribose) drives pathologic α-synuclein neurodegeneration in Parkinson’s disease. Science 362, eaat8407 (2018).
Abeti, R., Abramov, A. Y. & Duchen, M. R. β-Amyloid activates PARP causing astrocytic metabolic failure and neuronal death. Brain 134, 1658–1672 (2011).
Chidambaram, S. B. et al. Simultaneous blockade of NMDA receptors and PARP-1 activity synergistically alleviate immunoexcitotoxicity and bioenergetics in 3-nitropropionic acid intoxicated mice: evidences from memantine and 3-aminobenzamide interventions. Eur. J. Pharmacol. 803, 148–158 (2017).
Koehler, R. C., Dawson, V. L. & Dawson, T. M. Targeting parthanatos in ischemic stroke. Front. Neurol. 12, 662034 (2021).
Liu, S., Luo, W. & Wang, Y. Emerging role of PARP-1 and PARthanatos in ischemic stroke. J. Neurochem. 160, 74–87 (2021).
Kauppinen, T. M., Gan, L. & Swanson, R. A. Poly(ADP-ribose) polymerase-1-induced NAD+ depletion promotes nuclear factor-κB transcriptional activity by preventing p65 de-acetylation. Biochim. Biophys. Acta 1833, 1985–1991 (2013).
Friedlander, M. et al. Pamiparib in combination with tislelizumab in patients with advanced solid tumours: results from the dose-escalation stage of a multicentre, open-label, phase 1a/b trial. Lancet Oncol. 20, 1306–1315 (2019).
Yi, M. et al. Advances and perspectives of PARP inhibitors. Exp. Hematol. Oncol. 8, 29 (2019).
Ye, N. et al. Design, synthesis, and biological evaluation of a series of benzo[de][1,7]naphthyridin-7(8H)-ones bearing a functionalized longer chain appendage as novel PARP1 inhibitors. J. Med. Chem. 56, 2885–2903 (2013).
Jones, P. et al. Discovery of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (MK-4827): a novel oral poly(ADP-ribose)polymerase (PARP) inhibitor efficacious in BRCA-1 and -2 mutant tumors.J. Med. Chem. 52, 7170–7185 (2009).
Wang, B. et al. Discovery and characterization of (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one (BMN 673, Talazoparib), a novel, highly potent, and orally efficacious poly(ADP-ribose) polymerase-1/2 inhibitor, as an anticancer agent. J. Med. Chem. 59, 335–357 (2016).
Fatokun, A. A., Liu, J. O., Dawson, V. L. & Dawson, T. M. Identification through high-throughput screening of 4’-methoxyflavone and 3’,4’-dimethoxyflavone as novel neuroprotective inhibitors of parthanatos. Br. J. Pharmacol. 169, 1263–1278 (2013).
Calabrese, C. R. et al. Anticancer chemosensitization and radiosensitization by the novel poly(ADP-ribose) polymerase-1 inhibitor AG14361. J. Natl Cancer Inst. 96, 56–67 (2004).
Penning, T. D. et al. Optimization of phenyl-substituted benzimidazole carboxamide poly(ADP-ribose) polymerase inhibitors: identification of (S)-2-(2-fluoro-4-(pyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide (A-966492), a highly potent and efficacious inhibitor. J. Med. Chem. 53, 3142–3153 (2010).
Abdelkarim, G. E. et al. Protective effects of PJ34, a novel, potent inhibitor of poly(ADP-ribose) polymerase (PARP) in in vitro and in vivo models of stroke. Int. J. Mol. Med. 7, 255–260 (2001).
Hadian, K. & Stockwell, B. R. SnapShot: ferroptosis. Cell 181, 1188–1188.e1 (2020).
Stockwell, B. R. Ferroptosis turns 10: emerging mechanisms, physiological functions, and therapeutic applications. Cell 185, 2401–2421 (2022).
Dixon, S. J. et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149, 1060–1072 (2012).
Dolma, S., Lessnick, S. L., Hahn, W. C. & Stockwell, B. R. Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells. Cancer Cell 3, 285–296 (2003).
Yagoda, N. et al. RAS-RAF-MEK-dependent oxidative cell death involving voltage-dependent anion channels. Nature 447, 864–868 (2007).
Yang, W. S. & Stockwell, B. R. Synthetic lethal screening identifies compounds activating iron-dependent, nonapoptotic cell death in oncogenic-RAS-harboring cancer cells. Chem. Biol. 15, 234–245 (2008).
Seiler, A. et al. Glutathione peroxidase 4 senses and translates oxidative stress into 12/15-lipoxygenase dependent- and AIF-mediated cell death. Cell Metab. 8, 237–248 (2008).
Eagle, H. Nutrition needs of mammalian cells in tissue culture. Science 122, 501–514 (1955).
Brielmeier, M. et al. Cloning of phospholipid hydroperoxide glutathione peroxidase (PHGPx) as an anti-apoptotic and growth promoting gene of Burkitt lymphoma cells. Biofactors 14, 179–190 (2001).
Falk, M. H. et al. Apoptosis in Burkitt lymphoma cells is prevented by promotion of cysteine uptake. Int. J. Cancer 75, 620–625 (1998).
Friedmann Angeli, J. P. et al. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat. Cell Biol. 16, 1180–1191 (2014).
Tan, S., Schubert, D. & Maher, P. Oxytosis: a novel form of programmed cell death. Curr. Top. Med. Chem. 1, 497–506 (2001).
Doll, S. et al. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat. Chem. Biol. 13, 91–98 (2017).
Conrad, M. & Pratt, D. A. The chemical basis of ferroptosis. Nat. Chem. Biol. 15, 1137–1147 (2019).
Wenzel, S. E. et al. PEBP1 wardens ferroptosis by enabling lipoxygenase generation of lipid death signals. Cell 171, 628–641.e6 (2017).
Shah, R., Shchepinov, M. S. & Pratt, D. A. Resolving the role of lipoxygenases in the initiation and execution of ferroptosis. ACS Cent. Sci. 4, 387–396 (2018).
Zou, Y. et al. Cytochrome P450 oxidoreductase contributes to phospholipid peroxidation in ferroptosis. Nat. Chem. Biol. 16, 302–309 (2020).
Yan, B. et al. Membrane damage during ferroptosis is caused by oxidation of phospholipids catalyzed by the oxidoreductases POR and CYB5R1. Mol. Cell 81, 355–369.e10 (2021).
Zou, Y. et al. Plasticity of ether lipids promotes ferroptosis susceptibility and evasion. Nature 585, 603–608 (2020).
Zhang, H. L. et al. PKCβII phosphorylates ACSL4 to amplify lipid peroxidation to induce ferroptosis. Nat. Cell Biol. 24, 88–98 (2022).
Wu, J. et al. Intercellular interaction dictates cancer cell ferroptosis via NF2-YAP signalling. Nature 572, 402–406 (2019).
Miess, H. et al. The glutathione redox system is essential to prevent ferroptosis caused by impaired lipid metabolism in clear cell renal cell carcinoma. Oncogene 37, 5435–5450 (2018).
Zou, Y. et al. A GPX4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferroptosis. Nat. Commun. 10, 1617 (2019).
Lang, X. et al. Radiotherapy and immunotherapy promote tumoral lipid oxidation and ferroptosis via synergistic repression of SLC7A11. Cancer Discov. 9, 1673–1685 (2019).
Lei, G. et al. The role of ferroptosis in ionizing radiation-induced cell death and tumor suppression. Cell Res. 30, 146–162 (2020).
Ye, L. F. et al. Radiation-induced lipid peroxidation triggers ferroptosis and synergizes with ferroptosis inducers. ACS Chem. Biol. 15, 469–484 (2020).
Venkatesh, D. et al. MDM2 and MDMX promote ferroptosis by PPARα-mediated lipid remodeling. Genes Dev. 34, 526–543 (2020).
Stockwell, B. R. et al. Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell 171, 273–285 (2017).
Bannai, S. & Kitamura, E. Transport interaction of L-cystine and L-glutamate in human diploid fibroblasts in culture. J. Biol. Chem. 255, 2372–2376 (1980).
Sato, H., Tamba, M., Ishii, T. & Bannai, S. Cloning and expression of a plasma membrane cystine/glutamate exchange transporter composed of two distinct proteins. J. Biol. Chem. 274, 11455–11458 (1999).
Yang, W. S. et al. Regulation of ferroptotic cancer cell death by GPX4. Cell 156, 317–331 (2014).
Barayeu, U. et al. Hydropersulfides inhibit lipid peroxidation and ferroptosis by scavenging radicals. Nat. Chem. Biol. 19, 28–37 (2023).
Wu, Z. et al. Hydropersulfides inhibit lipid peroxidation and protect cells from ferroptosis. J. Am. Chem. Soc. 144, 15825–15837 (2022).
Dixon, S. J. & Stockwell, B. R. The hallmarks of ferroptosis. Annu. Rev. Cancer Biol. 3, 35–54 (2019).
Jiang, X., Stockwell, B. R. & Conrad, M. Ferroptosis: mechanisms, biology and role in disease. Nat. Rev. Mol. Cell Biol. 22, 266–282 (2021).
Freitas, F. P. et al. 7-Dehydrocholesterol is an endogenous suppressor of ferroptosis. Preprint at Research Square https://doi.org/10.21203/rs.3.rs-943221/v1 (2021).
Yamada, N. et al. DHCR7 as a novel regulator of ferroptosis in hepatocytes. Preprint at bioRxiv https://doi.org/10.1101/2022.06.15.496212 (2022).
Magtanong, L. et al. Exogenous monounsaturated fatty acids promote a ferroptosis-resistant cell state. Cell Chem. Biol. 26, 420–432.e9 (2019).
Bersuker, K. et al. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature 575, 688–692 (2019).
Doll, S. et al. FSP1 is a glutathione-independent ferroptosis suppressor. Nature 575, 693–698 (2019).
Mishima, E. et al. A non-canonical vitamin K cycle is a potent ferroptosis suppressor. Nature 608, 778–783 (2022).
Kraft, V. A. N. et al. GTP cyclohydrolase 1/tetrahydrobiopterin counteract ferroptosis through lipid remodeling. ACS Cent. Sci. 6, 41–53 (2020).
Soula, M. et al. Metabolic determinants of cancer cell sensitivity to canonical ferroptosis inducers. Nat. Chem. Biol. 16, 1351–1360 (2020).
Kim, D. H. et al. Farnesoid X receptor protects against cisplatin-induced acute kidney injury by regulating the transcription of ferroptosis-related genes. Redox Biol. 54, 102382 (2022).
Tschuck, J. et al. Farnesoid X receptor suppresses lipid peroxidation and ferroptosis. Preprint at bioRxiv https://doi.org/10.1101/2022.10.07.511245 (2022).
Sun, W. Y. et al. Phospholipase iPLA2β averts ferroptosis by eliminating a redox lipid death signal. Nat. Chem. Biol. 17, 465–476 (2021).
Chen, D. et al. iPLA2β-mediated lipid detoxification controls p53-driven ferroptosis independent of GPX4. Nat. Commun. 12, 3644 (2021).
Lee, H. et al. Energy-stress-mediated AMPK activation inhibits ferroptosis. Nat. Cell Biol. 22, 225–234 (2020).
Zhang, Y. et al. mTORC1 couples cyst(e)ine availability with GPX4 protein synthesis and ferroptosis regulation. Nat. Commun. 12, 1589 (2021).
Yi, J., Zhu, J., Wu, J., Thompson, C. B. & Jiang, X. Oncogenic activation of PI3K-AKT-mTOR signaling suppresses ferroptosis via SREBP-mediated lipogenesis. Proc. Natl Acad. Sci. USA 117, 31189–31197 (2020).
Conlon, M. et al. A compendium of kinetic modulatory profiles identifies ferroptosis regulators. Nat. Chem. Biol. 17, 665–674 (2021).
Brown, C. W. et al. Prominin2 drives ferroptosis resistance by stimulating iron export. Dev. Cell 51, 575–586.e4 (2019).
Brown, C. W., Chhoy, P., Mukhopadhyay, D., Karner, E. R. & Mercurio, A. M. Targeting prominin2 transcription to overcome ferroptosis resistance in cancer. EMBO Mol. Med. 13, e13792 (2021).
Angelova, P. R. et al. Alpha synuclein aggregation drives ferroptosis: an interplay of iron, calcium and lipid peroxidation. Cell Death Differ. 27, 2781–2796 (2020).
Skouta, R. et al. Ferrostatins inhibit oxidative lipid damage and cell death in diverse disease models. J. Am. Chem. Soc. 136, 4551–4556 (2014).
Hambright, W. S., Fonseca, R. S., Chen, L., Na, R. & Ran, Q. Ablation of ferroptosis regulator glutathione peroxidase 4 in forebrain neurons promotes cognitive impairment and neurodegeneration. Redox Biol. 12, 8–17 (2017).
Zhang, Y. H. et al. α-Lipoic acid improves abnormal behavior by mitigation of oxidative stress, inflammation, ferroptosis, and tauopathy in P301S Tau transgenic mice. Redox Biol. 14, 535–548 (2018).
Chen, L., Hambright, W. S., Na, R. & Ran, Q. Ablation of the ferroptosis inhibitor glutathione peroxidase 4 in neurons results in rapid motor neuron degeneration and paralysis. J. Biol. Chem. 290, 28097–28106 (2015).
Alim, I. et al. Selenium drives a transcriptional adaptive program to block ferroptosis and treat stroke. Cell 177, 1262–1279.e25 (2019).
Bao, Z. et al. Prokineticin-2 prevents neuronal cell deaths in a model of traumatic brain injury. Nat. Commun. 12, 4220 (2021).
Linkermann, A. et al. Synchronized renal tubular cell death involves ferroptosis. Proc. Natl Acad. Sci. USA 111, 16836–16841 (2014).
Tonnus, W. et al. Dysfunction of the key ferroptosis-surveilling systems hypersensitizes mice to tubular necrosis during acute kidney injury. Nat. Commun. 12, 4402 (2021).
Fang, X. et al. Loss of cardiac ferritin H facilitates cardiomyopathy via Slc7a11-mediated ferroptosis. Circ. Res. 127, 486–501 (2020).
Fang, X. et al. Ferroptosis as a target for protection against cardiomyopathy. Proc. Natl Acad. Sci. USA 116, 2672–2680 (2019).
Günes Günsel, G. et al. The arginine methyltransferase PRMT7 promotes extravasation of monocytes resulting in tissue injury in COPD. Nat. Commun. 13, 1303 (2022).
Conrad, M., Lorenz, S. M. & Proneth, B. Targeting ferroptosis: new hope for as-yet-incurable diseases. Trends Mol. Med. 27, 113–122 (2020).
Lei, G., Zhuang, L. & Gan, B. Targeting ferroptosis as a vulnerability in cancer. Nat. Rev. Cancer 22, 381–396 (2022).
Zhang, Y. et al. Imidazole ketone erastin induces ferroptosis and slows tumor growth in a mouse lymphoma model. Cell Chem. Biol. 26, 623–633.e9 (2019).
Ubellacker, J. M. et al. Lymph protects metastasizing melanoma cells from ferroptosis. Nature 585, 113–118 (2020).
Hong, X. et al. The lipogenic regulator SREBP2 induces transferrin in circulating melanoma cells and suppresses ferroptosis. Cancer Discov. 11, 678–695 (2021).
Dierge, E. et al. Peroxidation of n-3 and n-6 polyunsaturated fatty acids in the acidic tumor environment leads to ferroptosis-mediated anticancer effects. Cell Metab. 33, 1701–1715.e5 (2021).
Wang, W. M. et al. CD8+ T cells regulate tumour ferroptosis during cancer immunotherapy. Nature 569, 270–274 (2019).
Liao, P. et al. CD8+ T cells and fatty acids orchestrate tumor ferroptosis and immunity via ACSL4. Cancer Cell 40, 365–378.e6 (2022).
Xu, S. et al. Uptake of oxidized lipids by the scavenger receptor CD36 promotes lipid peroxidation and dysfunction in CD8+ T cells in tumors. Immunity 54, 1561–1577.e7 (2021).
Badgley, M. A. et al. Cysteine depletion induces pancreatic tumor ferroptosis in mice. Science 368, 85–89 (2020).
Gout, P. W., Buckley, A. R., Simms, C. R. & Bruchovsky, N. Sulfasalazine, a potent suppressor of lymphoma growth by inhibition of the xc- cystine transporter: a new action for an old drug. Leukemia 15, 1633–1640 (2001).
Dixon, S. J. et al. Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosis. eLife 3, e02523 (2014).
Zheng, J. et al. Sorafenib fails to trigger ferroptosis across a wide range of cancer cell lines. Cell Death Dis. 12, 698 (2021).
Weiwer, M. et al. Development of small-molecule probes that selectively kill cells induced to express mutant RAS. Bioorg. Med. Chem. Lett. 22, 1822–1826 (2012).
Eaton, J. K. et al. Selective covalent targeting of GPX4 using masked nitrile-oxide electrophiles. Nat. Chem. Biol. 16, 497–506 (2020).
Shimada, K. et al. Global survey of cell death mechanisms reveals metabolic regulation of ferroptosis. Nat. Chem. Biol. 12, 497–503 (2016).
Sun, Y. et al. Fin56-induced ferroptosis is supported by autophagy-mediated GPX4 degradation and functions synergistically with mTOR inhibition to kill bladder cancer cells. Cell Death Dis. 12, 1028 (2021).
Gaschler, M. M. et al. FINO2 initiates ferroptosis through GPX4 inactivation and iron oxidation. Nat. Chem. Biol. 14, 507–515 (2018).
Griffith, O. W. Mechanism of action, metabolism, and toxicity of buthionine sulfoximine and its higher homologs, potent inhibitors of glutathione synthesis. J. Biol. Chem. 257, 13704–13712 (1982).
Fruehauf, J. P. et al. Selective and synergistic activity of L-S,R-buthionine sulfoximine on malignant melanoma is accompanied by decreased expression of glutathione-S-transferase. Pigment. Cell Res. 10, 236–249 (1997).
Ding, Y., Fei, Y. & Lu, B. Emerging new concepts of degrader technologies. Trends Pharmacol. Sci. 41, 464–474 (2020).
Pettersson, M. & Crews, C. M. Proteolysis targeting chimeras (PROTACs) — past, present and future. Drug Discov. Today Technol. 31, 15–27 (2019).
Banik, S. M. et al. Lysosome-targeting chimaeras for degradation of extracellular proteins. Nature 584, 291–297 (2020).
Luo, T. et al. Intracellular delivery of glutathione peroxidase degrader induces ferroptosis in vivo. Angew. Chem. Int. Ed. Engl. 61, e202206277 (2022).
Hendricks, J. M. et al. Identification of structurally diverse FSP1 inhibitors that sensitize cancer cells to ferroptosis. Cell Chem. Biol. https://doi.org/10.1016/j.chembiol.2023.04.007 (2023).
Zilka, O. et al. On the mechanism of cytoprotection by ferrostatin-1 and liproxstatin-1 and the role of lipid peroxidation in ferroptotic cell death. ACS Cent. Sci. 3, 232–243 (2017).
Poon, J. F., Zilka, O. & Pratt, D. A. Potent ferroptosis inhibitors can catalyze the cross-dismutation of phospholipid-derived peroxyl radicals and hydroperoxyl radicals. J. Am. Chem. Soc. 142, 14331–14342 (2020).
Hofmans, S. et al. Novel ferroptosis inhibitors with improved potency and ADME properties. J. Med. Chem. 59, 2041–2053 (2016).
Devisscher, L. et al. Discovery of novel, drug-like ferroptosis inhibitors with in vivo efficacy. J. Med. Chem. 61, 10126–10140 (2018).
Anthonymuthu, T. S. et al. Resolving the paradox of ferroptotic cell death: Ferrostatin-1 binds to 15LOX/PEBP1 complex, suppresses generation of peroxidized ETE-PE, and protects against ferroptosis. Redox Biol. 38, 101744 (2021).
Tsvetkov, P. et al. Copper induces cell death by targeting lipoylated TCA cycle proteins. Science 375, 1254–1261 (2022).
Du, W. et al. Lysosomal Zn2+ release triggers rapid, mitochondria-mediated, non-apoptotic cell death in metastatic melanoma. Cell Rep. 37, 109848 (2021).
Lichtmannegger, J. et al. Methanobactin reverses acute liver failure in a rat model of Wilson disease. J. Clin. Invest. 126, 2721–2735 (2016).
Liu, X. et al. Actin cytoskeleton vulnerability to disulfide stress mediates disulfidptosis. Nat. Cell Biol. 25, 404–414 (2023).
Samarasinghe, K. T. G. et al. Targeted degradation of transcription factors by TRAFTACs: transcription factor targeting chimeras. Cell Chem. Biol. 28, 648–661.e5 (2021).
Henning, N. J. et al. Deubiquitinase-targeting chimeras for targeted protein stabilization. Nat. Chem. Biol. 18, 412–421 (2022).
Lewerenz, J., Ates, G., Methner, A., Conrad, M. & Maher, P. Oxytosis/ferroptosis-(Re-) emerging roles for oxidative stress-dependent non-apoptotic cell death in diseases of the central nervous system. Front. Neurosci. 12, 214 (2018).
Pedrera, L. et al. Ferroptotic pores induce Ca2+ fluxes and ESCRT-III activation to modulate cell death kinetics. Cell Death Differ. 28, 1644–1657 (2021).
Xin, S. et al. MS4A15 drives ferroptosis resistance through calcium-restricted lipid remodeling. Cell Death Differ. 29, 670–686 (2022).
Murphy, T. H., Malouf, A. T., Sastre, A., Schnaar, R. L. & Coyle, J. T. Calcium-dependent glutamate cytotoxicity in a neuronal cell line. Brain Res. 444, 325–332 (1988).
Li, Y., Maher, P. & Schubert, D. A role for 12-lipoxygenase in nerve cell death caused by glutathione depletion. Neuron 19, 453–463 (1997).
Grabbe, C., Husnjak, K. & Dikic, I. The spatial and temporal organization of ubiquitin networks. Nat. Rev. Mol. Cell Biol. 12, 295–307 (2011).
Dondelinger, Y., Darding, M., Bertrand, M. J. & Walczak, H. Poly-ubiquitination in TNFR1-mediated necroptosis. Cell Mol. Life Sci. 73, 2165–2176 (2016).
Seo, J. et al. CHIP controls necroptosis through ubiquitylation- and lysosome-dependent degradation of RIPK3. Nat. Cell Biol. 18, 291–302 (2016).
Choi, S. W. et al. PELI1 selectively targets kinase-active RIP3 for ubiquitylation-dependent proteasomal degradation. Mol. Cell 70, 920–935.e7 (2018).
Mei, P. et al. E3 ligase TRIM25 ubiquitinates RIP3 to inhibit TNF induced cell necrosis. Cell Death Differ. 28, 2888–2899 (2021).
Humphries, F. et al. The E3 ubiquitin ligase Pellino2 mediates priming of the NLRP3 inflammasome. Nat. Commun. 9, 1560 (2018).
Guo, Y. et al. HUWE1 mediates inflammasome activation and promotes host defense against bacterial infection. J. Clin. Invest. 130, 6301–6316 (2020).
Han, S. et al. Lipopolysaccharide primes the NALP3 inflammasome by inhibiting its ubiquitination and degradation mediated by the SCFFBXL2 E3 ligase. J. Biol. Chem. 290, 18124–18133 (2015).
Yan, Y. et al. Dopamine controls systemic inflammation through inhibition of NLRP3 inflammasome. Cell 160, 62–73 (2015).
Song, H. et al. The E3 ubiquitin ligase TRIM31 attenuates NLRP3 inflammasome activation by promoting proteasomal degradation of NLRP3. Nat. Commun. 7, 13727 (2016).
Tang, T. et al. The E3 ubiquitin ligase TRIM65 negatively regulates inflammasome activation through promoting ubiquitination of NLRP3. Front. Immunol. 12, 741839 (2021).
Kawashima, A. et al. ARIH2 ubiquitinates NLRP3 and negatively regulates NLRP3 inflammasome activation in macrophages. J. Immunol. 199, 3614–3622 (2017).
Tang, J. et al. Sequential ubiquitination of NLRP3 by RNF125 and Cbl-b limits inflammasome activation and endotoxemia. J. Exp. Med. 217, e20182091 (2020).
Py, B. F., Kim, M. S., Vakifahmetoglu-Norberg, H. & Yuan, J. Deubiquitination of NLRP3 by BRCC3 critically regulates inflammasome activity. Mol. Cell 49, 331–338 (2013).
Palazón-Riquelme, P. et al. USP7 and USP47 deubiquitinases regulate NLRP3 inflammasome activation. EMBO Rep. 19, e44766 (2018).
Song, H. et al. UAF1 deubiquitinase complexes facilitate NLRP3 inflammasome activation by promoting NLRP3 expression. Nat. Commun. 11, 6042 (2020).
Suzuki, T., Motohashi, H. & Yamamoto, M. Toward clinical application of the Keap1-Nrf2 pathway. Trends Pharmacol. Sci. 34, 340–346 (2013).
Lu, M. C. et al. CPUY192018, a potent inhibitor of the Keap1-Nrf2 protein-protein interaction, alleviates renal inflammation in mice by restricting oxidative stress and NF-κB activation. Redox Biol. 26, 101266 (2019).
Zhang, Y. et al. BAP1 links metabolic regulation of ferroptosis to tumour suppression. Nat. Cell Biol. 20, 1181–1192 (2018).
Liu, T., Jiang, L., Tavana, O. & Gu, W. The deubiquitylase OTUB1 mediates ferroptosis via stabilization of SLC7A11. Cancer Res. 79, 1913–1924 (2019).
Acknowledgements
B.R.S. is supported by NCI grant R35CA209896 and NINDS grant R33NS109407.
Author information
Authors and Affiliations
Contributions
Both authors contributed equally to all aspects of the article.
Corresponding authors
Ethics declarations
Competing interests
B.R.S. is an inventor on patents and patent applications involving ferroptosis, holds equity in and serves as a consultant to Exarta Therapeutics and ProJenX Inc., holds equity in Sonata Therapeutics, and serves as a consultant to Weatherwax Biotechnologies Corporation and Akin Gump Strauss Hauer & Feld LLP. K.H. is an inventor on a patent application involving ferroptosis.
Peer review
Peer review information
Nature Reviews Drug Discovery thanks José Pedro Friedmann Angeli, Boyi Gan and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Hadian, K., Stockwell, B.R. The therapeutic potential of targeting regulated non-apoptotic cell death. Nat Rev Drug Discov 22, 723–742 (2023). https://doi.org/10.1038/s41573-023-00749-8
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41573-023-00749-8
This article is cited by
-
Machine learning-driven prognostic analysis of cuproptosis and disulfidptosis-related lncRNAs in clear cell renal cell carcinoma: a step towards precision oncology
European Journal of Medical Research (2024)
-
Osteoking promotes bone formation and bone defect repair through ZBP1–STAT1–PKR–MLKL-mediated necroptosis
Chinese Medicine (2024)
-
Targeting immunogenic cell stress and death for cancer therapy
Nature Reviews Drug Discovery (2024)
-
The death gaze of MEDUSA
Nature Chemical Biology (2024)
-
Highly expressed RPLP2 inhibits ferroptosis to promote hepatocellular carcinoma progression and predicts poor prognosis
Cancer Cell International (2023)
