bims-cediti Biomed News
on Cell death in innate immunity, inflammation, and tissue repair
Issue of 2025–10–19
fourteen papers selected by
Kateryna Shkarina, Universität Bonn
  1. S-Palmitoylation regulates signaling mediated by NLRP3 and other innate immune receptors.
  2. NLRP1 under pressure: An overview of the NLRP1 inflammasome as a sensor of cellular stress.
  3. The formation of the 'footprint of death' as a mechanism for generating large substrate-bound extracellular vesicles that mark the site of cell death.
  4. Discovery of NP3-742: A Structurally Diverse NLRP3 Inhibitor Identified through an Unusual Phenol Replacement.
  5. Necroptotic cell death consequences and disease relevance.
  6. MAPL regulates gasdermin-mediated release of mtDNA from lysosomes to drive pyroptotic cell death.
  7. Cleavage of Bcl-2-associated athanogene by metacaspase determines plant antiviral immunity.
  8. Nucleic acid-protein condensates in innate immunity.
  9. Adenosine metabolic clearance maintains liver homeostasis by licensing arginine methylation of RIPK1.
  10. Chemically induced dimerization of GSDMD C-terminal domain blocks GSDMD N-terminal domain-mediated pyroptosis.
  11. DAMPs in the immunogenicity of cell death.
  12. Host cell Z-RNAs activate ZBP1 during virus infections.
  13. Exploiting metabolic cell death for cancer therapy.
  14. Cell-death networks.
  1. Mol Cell. 2025 Oct 16. pii: S1097-2765(25)00750-6. [Epub ahead of print]85(20): 3862-3873
    S-Palmitoylation regulates signaling mediated by NLRP3 and other innate immune receptors.
    Eugene Varfolomeev, Vishnu Mohanan, Domagoj Vucic.
      The innate immune system coordinates the immediate response to microbial pathogens and tissue damage to allow pathogen clearance and tissue repair. Pathogen recognition receptors (PRRs) recognize danger- and pathogen-associated molecular patterns to trigger immune signaling. The PRR NLRP3 is activated by inflammatory stimuli to instigate the formation of the NLRP3-associated inflammasome. Emerging data highlight the importance of S-palmitoylation (or S-acylation) for NLRP3 activation. Several protein acyltransferases promote NLRP3 S-palmitoylation at a distinct set of cysteine residues to regulate assembly and intracellular localization of the NLRP3 inflammasome. S-Palmitoylation of gasdermin D (GSDMD) and other mediators of innate immunity, including NOD2, Toll-like receptors (TLRs), and stimulator of interferon gene (STING), also modulates immune responses and inflammatory cell death. However, the physiological implication of these S-palmitoylation events has not been established yet, and S-palmitoylation can have a negative effect on inflammatory signaling as well. This review outlines the key features of S-palmitoylation in innate immune signaling and highlights the unresolved questions.
    Keywords:  GSDMD; NLRP3; S-palmitoylation; inflammasome; pyroptosis; zDHHC
    DOI:  https://doi.org/10.1016/j.molcel.2025.09.009
  2. Mol Cell. 2025 Oct 16. pii: S1097-2765(25)00778-6. [Epub ahead of print]85(20): 3853-3861
    NLRP1 under pressure: An overview of the NLRP1 inflammasome as a sensor of cellular stress.
    Jeremy Kean Yi Yap, Kinga Duszyc, Kate Schroder.
      NLRP1 (NACHT, leucine-rich repeats [LRRs], and pyrin domain [PYD]-containing protein 1) is a microbe and stress sensor that, upon activation, forms a caspase-1-activating inflammasome that drives IL-1β and IL-18 maturation and pyroptotic cell death. NLRP1 exhibits allelic diversity and interspecies differences in protein architecture, activating stimuli and expression patterns. Despite this complexity, human NLRP1 is emerging as an important sensor of perturbations in epithelial homeostasis, with key functions in epithelial inflammation, integrity, and barrier function. Here, we review recent discoveries of NLRP1 activation pathways, insights that may be gained from the related proteins caspase recruitment domain 8 (CARD8) and PIDD1, and open questions that continue to challenge the field as we move toward greater understanding of this enigmatic signaling pathway.
    Keywords:  CADR8; NLRP1; PIDD; apoptosis; epithelia; inflammasome; inflammation; pyroptosis
    DOI:  https://doi.org/10.1016/j.molcel.2025.09.018
  3. Nat Commun. 2025 Oct 15. 16(1): 9160
    The formation of the 'footprint of death' as a mechanism for generating large substrate-bound extracellular vesicles that mark the site of cell death.
    Stephanie F Rutter, Taeyoung Kang, Gemma F Ryan, Bo Shi, Caitlin L Vella, Pradeep Rajasekhar, Sean W Cutter, Amy L Hodge, Dilara C Ozkocak, Ching-Seng Ang, Julian Ratcliffe, Katrina J Binger, Pamali Foneska, Suresh Mathivanan, Niall D Geoghegan, Kelly L Rogers, Michael F Olson, Georgia K Atkin-Smith, Ivan K H Poon.
      Apoptotic cells communicate to phagocytic cells through releasing soluble factors and apoptotic cell-derived extracellular vesicles. However, whether there are additional factors that remain attached at the site of cell death to signal to phagocytic cells is currently unknown. Here we show that apoptotic cell retraction generates a membrane-encased, F-actin-rich 'footprint' tightly anchored to the substrate that marks the site of cell death, coined 'the FOotprint Of Death' or FOOD. Formation of FOOD is observed frequently across many different cell types, apoptotic stimuli and surface composition. Mechanistically, FOOD formation is regulated by the protein kinase ROCK1. 3D time-lapse microscopy studies revealed that FOOD vesicularises into distinct large extracellular vesicles. These extracellular vesicles expose the 'eat-me' signal phosphatidylserine and can function to 'flag' the site of cell death to neighbouring phagocytes for efferocytosis. Under a viral infection setting, FOOD can harbour viral proteins and virions, and propagate infection to healthy cells. Together, this study has revealed another route of apoptotic cell-phagocyte communication.
    DOI:  https://doi.org/10.1038/s41467-025-64206-3
  4. J Med Chem. 2025 Oct 15.
    Discovery of NP3-742: A Structurally Diverse NLRP3 Inhibitor Identified through an Unusual Phenol Replacement.
    Juraj Velcicky, Jean-Baptiste Langlois, Michael Wright, Philipp Janser, Daniela Angst, Christelle Arnold, Karen Beltz, Silke Brenneisen, Celine Dubois, Janet Dawson, Christian Fischer, Nina Gommermann, Andreas Heizmann, Slavica Ilic, Rainer Machauer, Magdalena Maschlej, Sarah Monnerat, Daniel Pflieger, Jacinda Ristov, Joelle Rubert, Günther Schwalm, Daniel R Smith, Honnappa Srinivas, Roland Steiner, Aleksandar Stojanovic, Thomas Troxler, Adeline Unterreiner, Eric Vangrevelinghe, Nicole von Burg, Jennifer Wunderlich, Christopher J Farady, Angela Mackay.
      NLRP3 is a molecular sensor present in innate immune cells which recognizes a variety of danger signals such as MSU, ATP, or Aβ. Upon activation, it seeds a protein complex termed the inflammasome, which leads to secretion of the proinflammatory cytokines IL-1β and IL-18 and initiates pyroptotic cell death. NLRP3 inflammasome activation has been associated with a wide range of diseases including atherosclerosis, gout, and cancer. In this publication, we describe the replacement of the phenol moiety with indoles in the recently described pyridazine scaffold. This replacement required a shift of the hydrogen bond donor from the "ortho" to the "meta" position, relative to the pyridazine ring. Initial indole analog 7 demonstrated a robust in vivo IL-1β inhibition, but also a significant hERG inhibition. Decreasing lipophilicity led to the discovery of NP3-742, demonstrating a favorable overall profile including diminished hERG inhibition and in vivo efficacy in a mouse peritonitis model.
    DOI:  https://doi.org/10.1021/acs.jmedchem.5c02412
  5. Nat Immunol. 2025 Oct 15.
    Necroptotic cell death consequences and disease relevance.
    James E Vince, Nadia M Davidson, Maria C Tanzer.
      Arguably one of the most surprising revelations in the field of cell death research was the discovery that cellular necrosis, a lytic and inherently messy cell death with far-reaching consequences for human physiology, can be genetically encoded. There is no single necrotic pathway either, as compelling evidence exists for distinct necrotic modalities such as pyroptosis, necroptosis and ferroptosis. The recent momentum of molecular, structural and disease-relevant findings has opened the door to targeting necrotic machinery to prevent collateral tissue damage and inflammatory diseases. In this Review, we evaluate the case for targeting the necrotic cell death pathway called necroptosis. We examine the organs and cell types where the human necroptotic machinery is expressed, identifying a lymphocytic ZBP1, RIPK1, RIPK3 and MLKL signature, review knowledge into the immunogenic consequences of necroptotic signaling and highlight building evidence that necroptosis is engaged in humans and can be triggered by ischemic injuries. Finally, we note several limitations of mouse studies due to fundamental differences with the human necroptotic apparatus and critically appraise the evidence for necroptosis being a disease-driving factor that, if successfully targeted, could be of clinical benefit.
    DOI:  https://doi.org/10.1038/s41590-025-02298-1
  6. Nat Cell Biol. 2025 Oct;27(10): 1708-1724
    MAPL regulates gasdermin-mediated release of mtDNA from lysosomes to drive pyroptotic cell death.
    Mai Nguyen, Jack J Collier, Olesia Ignatenko, Genevieve Morin, Vanessa Goyon, Alexandre Janer, Camila Tiefensee Ribeiro, Austen J Milnerwood, Sidong Huang, Michel Desjardins, Heidi M McBride.
      Mitochondrial control of cell death is of central importance to disease mechanisms from cancer to neurodegeneration. Mitochondrial anchored protein ligase (MAPL) is an outer mitochondrial membrane small ubiquitin-like modifier ligase that is a key determinant of cell survival, yet how MAPL controls the fate of this process remains unclear. Combining genome-wide functional genetic screening and cell biological approaches, we found that MAPL induces pyroptosis through an inflammatory pathway involving mitochondria and lysosomes. MAPL overexpression promotes mitochondrial DNA trafficking in mitochondrial-derived vesicles to lysosomes, which are permeabilized in a process requiring gasdermin pores. This triggers the release of mtDNA into the cytosol, activating the DNA sensor cGAS, required for cell death. Additionally, multiple Parkinson's disease-related genes, including VPS35 and LRRK2, also regulate MAPL-induced pyroptosis. Notably, depletion of MAPL, LRRK2 or VPS35 inhibited inflammatory cell death in primary macrophages, placing MAPL and the mitochondria-lysosome pathway at the nexus of immune signalling and cell death.
    DOI:  https://doi.org/10.1038/s41556-025-01774-y
  7. Nat Commun. 2025 Oct 14. 16(1): 9102
    Cleavage of Bcl-2-associated athanogene by metacaspase determines plant antiviral immunity.
    Lin Liang, Yuhang Jiang, Pingzhi Zhao, Hongwei Wang, Xiaoyue Chen, Xiao Lin, Yanwei Sun, Wenqian Zhang, Rongxiang Fang, Jian Ye.
      Nucleotide-binding leucine-rich repeat receptors (NLRs) function as core components of innate immunity in both plants and animals. In animals, NLR activation initiates caspase-mediated immune signaling. In contrast, plants lack caspases but instead contain metacaspases (MCAs/MCs), yet their role in antiviral immunity and whether they interface with NLR signaling remain largely unexplored. Here, we demonstrate that cleavage of the conserved immune regulator Bcl-2-associated athanogene 3 (BAG3) by metacaspase 4 (MCAIIa/MC4) induces cell death and activates antiviral immunity in plants. Upon Begomovirus infection, MC4 cleaves BAG3 to release its N-terminal functional domain (BAG3-N) from autoinhibition. BAG3-N assembles into oligomers and induces cell death, effectively inhibiting viral replication. This signaling also interfaces with NLR networks in certain plant species. Viral replication-associated proteins (Reps) counteract this defense response by binding to BAG3-N, highlighting an evolutionary arms race between plants and viruses. Evolutionary analyses reveal that a lysine substitution at position 50 of BAG3 confers its ability to induce cell death in angiosperms. These findings identify BAG3 as a conserved immune regulator linking metacaspase activation to antiviral defense, providing a mechanistic basis for engineering crops with enhanced resistance to insect-borne viruses.
    DOI:  https://doi.org/10.1038/s41467-025-64021-w
  8. Mol Cell. 2025 Oct 16. pii: S1097-2765(25)00774-9. [Epub ahead of print]85(20): 3823-3839
    Nucleic acid-protein condensates in innate immunity.
    Gaia Loucas, Nicolas Locker, Roy Parker.
      Mammalian cells combat pathogens by diverse mechanisms. A key aspect of host defense is the pattern recognition receptors (PRRs) that recognize foreign nucleic acids and activate innate immune signaling pathways. Dysregulation of innate immunity is associated with both infectious diseases and chronic inflammatory conditions. Recent results argue that recognition of, and signaling from, foreign nucleic acids can be modulated by the concentration of PRRs and their nucleic acid ligands into RNA/DNA-protein co-condensates. Such condensates can affect the initiation of distinct cell death programs, proinflammatory signaling, host shutdown, and the innate immune response. Given these roles, hosts and pathogens have evolved to promote or antagonize PRR-nucleic acid condensation. Moreover, general ribonucleoprotein (RNP) granules such as stress granules and paraspeckles can either promote the formation of double-stranded RNA (dsRNA) and/or influence the response to foreign nucleic acids. Herein, we discuss advances in the field that address the relationship between RNA/DNA-protein co-condensates and innate immune regulation.
    DOI:  https://doi.org/10.1016/j.molcel.2025.09.014
  9. J Exp Med. 2026 Jan 05. pii: e20250603. [Epub ahead of print]223(1):
    Adenosine metabolic clearance maintains liver homeostasis by licensing arginine methylation of RIPK1.
    Ran Liu, Gengqiao Wang, Zhengting Jiang, Tianhao Zou, Chuanzheng Wang, Weimin Wang, Mao Cai, Shuhua Zhang, Guoliang Wang, Huan Cao, Di Zhang, Xueling Wang, Shenghe Deng, Tongxi Li, Jinyang Gu.
      Tumor necrosis factor α (TNFα) maintains homeostasis through promoting cell survival or cell death; however, how this process is regulated by metabolic pathways remains largely unknown. Here, we identify adenosine kinase (ADK), the key enzyme for catalyzing the conversion of adenosine to AMP, as an endogenous suppressor of RIPK1 kinase. ADK-mediated adenosine metabolic clearance is a prerequisite for transmethylation reactions on various cellular targets. We found that ADK licenses constitutive R606 symmetric dimethylation in RIPK1 death domain (DD), which is catalyzed by protein arginine methyltransferase 5. Upon TNFα stimulation, DD-mediated RIPK1 dimerization is inhibited by R606 methylation, preventing RIPK1 kinase activation and keeping cell death in check. Both hepatocyte-specific ADK knockout and systemic ADK inhibition cause spontaneous RIPK1-driven hepatocyte death, which leads to hepatic homeostasis disruption. Furthermore, ADK is reduced in hepatic ischemia-reperfusion, aggravating hepatic injury during liver surgery. Thus, this study reveals a mechanism of adenosine metabolism-dependent homeostasis maintenance that is implicated in both physiological and pathological conditions.
    DOI:  https://doi.org/10.1084/jem.20250603
  10. Cell Death Discov. 2025 Oct 13. 11(1): 456
    Chemically induced dimerization of GSDMD C-terminal domain blocks GSDMD N-terminal domain-mediated pyroptosis.
    Jixuan Xu, Miaoran Fu, Yamin Xing, Wulong Liang, Guangyuan Li, Ting Zhang, Mengxue Li, Chunxiao Gao, Zhanfeng Yang, Yuming Fu, Min Zhang, Zisen Zhang, Pengyuan Zheng, Xiufeng Chu.
      GSDMD is a pyroptosis executioner in which the C-terminal domain completely inhibits the pore-forming ability of the N-terminal domain. Caspase cleavage separates GSDMD into the free C-terminal fragment (GD-CT) and the free N-terminal fragment (GD-NT). Although GD-CT retains the ability to bind with GD-NT, it can no longer completely disable GD-NT, allowing the latter to oligomerize and form nano-sized pyroptotic pores in the plasma membrane. In this study, we report that GD-CT is strictly confined to the cytoplasm, whereas GD-NT is transported to the plasma membrane. Additionally, GD-CT undergoes rapid degradation via the 26S proteasome pathway. Therefore, we propose that the spatial separation and rapid turnover of GD-CT limit its efficacy in blocking GD-NT-mediated pyroptosis. Given these properties of GD-CT, we engineered an efficient pyroptosis blocker "FKBP-GD-CT". This chimera protein incorporates a myristoylation motif, which confers plasma membrane translocation capability, and an FKBP12F36V domain, which enables dimerization in response to the chemical inducer AP20187. This is the first report utilizing chemical-induced dimerization technology to modulate pyroptosis levels.
    DOI:  https://doi.org/10.1038/s41420-025-02733-0
  11. Mol Cell. 2025 Oct 16. pii: S1097-2765(25)00748-8. [Epub ahead of print]85(20): 3874-3889
    DAMPs in the immunogenicity of cell death.
    Ruochan Chen, Ju Zou, Jiao Liu, Rui Kang, Daolin Tang.
      Damage-associated molecular patterns (DAMPs) are endogenous molecules-such as proteins, lipids, and nucleic acids-released or exposed during cellular injury or stress, which shape immune responses by engaging danger sensors on the cell surface or within the cell interior. Recent advances have elucidated molecular links between distinct cell death pathways-apoptosis, necroptosis, pyroptosis, and ferroptosis-and DAMP release, emphasizing how biochemical features (e.g., posttranslational modifications) and temporal dynamics influence immunogenic versus tolerogenic outcomes. Here, we summarize these mechanisms, including both immunostimulatory and immunosuppressive DAMPs, and review key DAMP receptors-such as TLRs, NLRs, cGAS, and advanced glycosylation end-product-specific receptor (AGER)/RAGE-along with their downstream signaling cascades. Finally, we highlight emerging strategies to modulate DAMP signaling for cancer immunotherapy and the treatment of inflammatory diseases.
    Keywords:  DAMP receptors; DAMPs; ICD; cell death; immunotherapy
    DOI:  https://doi.org/10.1016/j.molcel.2025.09.007
  12. Nature. 2025 Oct 13.
    Host cell Z-RNAs activate ZBP1 during virus infections.
    Chaoran Yin, Aleksandr Fedorov, Hongyan Guo, Jeremy Chase Crawford, Claire Rousseau, Xiao Zhong, Riley M Williams, Avishekh Gautam, Heather S Koehler, Adam W Whisnant, Thomas Hennig, Anna Rozina, Yuhan Zhong, Shuangjuan Lv, Valter Bergant, Shuqi Wang, Peter Dröge, Sven Miller, Maria Poptsova, Jan Rehwinkel, Andreas Pichlmair, Edward S Mocarski, Paul G Thomas, Lars Dölken, Ting Zhang, Alan Herbert, Siddharth Balachandran.
      Herpes simplex virus 1 (HSV-1) and Influenza A viruses (IAV) induce Z-form nucleic acid Binding Protein 1 (ZBP1)-initiated cell death1-8. ZBP1 is activated by Z-RNA1,7,9, and the Z-RNAs which trigger ZBP1 during HSV-1 and IAV infections were assumed to be of viral origin1. However, we show here that host cell-encoded Z-RNAs are major and sufficient ZBP1 activating ligands following infection by these two human pathogens. The majority of cellular Z-RNAs mapped to intergenic endogenous retroelements (EREs) embedded within abnormally long 3' extensions of host cell mRNAs. These aberrant host cell transcripts arose as a consequence of Disruption of Transcription Termination (DoTT), a virus-driven phenomenon which disables Cleavage and Polyadenylation Specificity Factor (CPSF)-mediated 3' processing of nascent pre-mRNAs10-15. Mutant viruses lacking ICP27 or NS1, the virus-encoded proteins responsible for inhibiting CPSF and triggering DoTT13,15, failed to induce host cell Z-RNA accrual and were attenuated in their ability to stimulate ZBP1. Ectopic expression of HSV-1 ICP27 or IAV NS1, or pharmacological blockade of CPSF activity, induced accumulation of host cell Z-RNAs and activated ZBP1. These results demonstrate that DoTT-generated cellular Z-RNAs are bona fide ZBP1 ligands, and position ZBP1-activated cell death as a host response to counter viral disruption of the cellular transcriptional machinery.
    DOI:  https://doi.org/10.1038/s41586-025-09705-5
  13. Nat Rev Cancer. 2025 Oct 15.
    Exploiting metabolic cell death for cancer therapy.
    Chao Mao, Dadi Jiang, Albert C Koong, Boyi Gan.
      Resistance to cell death is a hallmark of cancer, driving tumour progression and limiting therapeutic efficacy. Metabolic cell death pathways have been identified as unique vulnerabilities in cancer, with ferroptosis being the most extensively studied, alongside the more recently discovered pathways of cuproptosis and disulfidptosis - each triggered by distinct metabolic perturbations. In this Review, we examine the molecular mechanisms and regulatory networks that govern these forms of metabolic cell death in cancer cells. We further examine the potential crosstalk between these pathways and discuss how insights gained and challenges encountered from extensive studies on ferroptosis can guide future research and therapeutic strategies targeting cuproptosis and disulfidptosis in cancer treatment. We highlight the complexity and dual roles of metabolic cell death in cancer and offer our perspective on how to leverage these cell death processes to develop innovative, targeted cancer therapies.
    DOI:  https://doi.org/10.1038/s41568-025-00879-8
  14. Mol Cell. 2025 Oct 16. pii: S1097-2765(25)00788-9. [Epub ahead of print]85(20): 3890-3890.e1
    Cell-death networks.
    Hamid Kashkar, Manolis Pasparakis.
      Cells can undergo death through various genetically regulated pathways, each leading to distinct tissue outcomes. Emerging evidence suggests that these pathways are molecularly interconnected, indicating that the mode of death is determined not only by apical signals but by the availability of terminal executioners/substrates. This evolving understanding challenges the traditional rigid classification of cell death and has important implications for its therapeutic targeting in diseases.
    DOI:  https://doi.org/10.1016/j.molcel.2025.09.028
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