bims-cediti Biomed News
on Cell death in innate immunity, inflammation, and tissue repair
Issue of 2026–08–09
thirteen papers selected by
Kateryna Shkarina, Universität Bonn
  1. The dynamic and heterogeneous structure of the non-canonical inflammasome.
  2. Candida albicans activates Staphylococcus aureus virulence regulatory systems to drive toxin-mediated human cell death.
  3. A Distinct c-Raf-MEK1/2-p38 MAPK-Caspase Signaling Pathway Mediates TNF-α-Induced Rapid and Non-Lytic Neutrophil Extracellular Trap Formation in Human Neutrophil-Like Cells.
  4. A genotype-first approach reveals the molecular basis of pyrin inflammasome activation.
  5. An autoinflammatory CDC42 variant M45L demonstrates the mechanism of pyrin inflammasome activation.
  6. An N-terminal CDC42 T43I variant reveals the mechanism of pyrin inflammasome activation.
  7. A bacterial fatty acid enzyme hijacks nucleic acid-sensing Toll-like receptor signaling.
  8. The anti-tumour activity of TNF in melanoma is determined by cFLIP.
  9. Circulating cochlin LCCL domain binds to dying cells and enhances efferocytosis.
  10. Ferroptosis spreading through propagative signals.
  11. IL-33 promotes efferocytosis by peritoneal macrophages by a mechanism associated with rapid granulocyte IL-13 production.
  12. Damage recognition by intestinal stem cells via Draper promotes adult Drosophila midgut regeneration.
  13. Virus-induced deconjugation of ISG15 dysregulates innate immunity and cellular metabolism.
  1. Proc Natl Acad Sci U S A. 2026 Aug 11. 123(32): e2613431123
    The dynamic and heterogeneous structure of the non-canonical inflammasome.
    Alexander I M Sever, James M Aramini, Jeffrey P Bonin, Huaying Zhao, Hanlin Wang, John L Rubinstein, Peter Schuck, Lewis E Kay.
      Inflammasomes are high-molecular-weight complexes that play integral roles in the innate immune system, triggering an inflammatory cascade to protect against cellular stresses such as pathogenic bacteria. Both canonical and non-canonical inflammasomes have been described in the literature and detailed structural studies of many components of the more complex and larger canonical versions have been reported. In contrast, corresponding structures of the non-canonical inflammasome have not emerged even though it consists of only two components: lipopolysaccharide (LPS) from Gram-negative bacteria and one of caspase-4 or caspase-5 in humans or caspase-11 in mice. Here, we determine the stoichiometry of the non-canonical inflammasome showing that it is heterogeneous, comprised of three major complexes with different numbers of LPS and caspase molecules. NMR spectroscopy studies of the N-terminal caspase activation and recruitment domain (CARD) of caspase-11, which binds LPS, establish that it is largely unstructured in the absence of lipid, with pervasive dynamics on the µs-ms timescale. Formation of this complex increases the α-helical content of the CARD, but the dynamics persist, multiple conformers are formed, and tertiary contacts are transient. The NMR results presented establish that the protease domain of caspase-11 is monomeric in isolation. As proteolysis is linked with dimerization, the protease domains are inactive in this state, but upon formation of the non-canonical inflammasome, dimerization occurs, priming the complex for rapid processing of substrates. Our study highlights the utility of NMR for studies of heterogeneous systems that are recalcitrant to crystallographic or cryo-EM analyses.
    Keywords:  NMR spectroscopy; caspase-11; effective concentration; non-canonical inflammasome; pyroptosis
    DOI:  https://doi.org/10.1073/pnas.2613431123
  2. PLoS Pathog. 2026 Aug 05. 22(8): e1014490
    Candida albicans activates Staphylococcus aureus virulence regulatory systems to drive toxin-mediated human cell death.
    Kara R Eichelberger, Ravishankar Chandrasekaran, Nicholas A Podar, Jia A Mei, Jacob M Curry, Saikat Paul, Julie A Bastarache, Victor J Torres, Paul L Fidel, Brian M Peters, James E Cassat.
      Co-infection with Staphylococcus aureus and Candida albicans leads to worsened disease severity compared to mono-microbial infection. Because our understanding of the mechanisms driving enhanced disease severity during co-infection is incomplete, we sought to evaluate how interactions with C. albicans regulate S. aureus virulence toward host cells. We determined that C. albicans enhances S. aureus cytotoxicity toward both murine and human monocytes. These data revealed that enhanced murine monocyte cell death requires the S. aureus Agr virulence regulatory system, and cell death is driven by α-type phenol soluble modulins and γ-hemolysin. Unexpectedly, upon testing human monocytes we discovered that C. albicans induces robust cytotoxicity of an S. aureus agr mutant (Δagr), which is completely non-toxic in mono-culture and toward murine cells. Human neutrophils are also susceptible to this cytotoxicity. Using reporter strains and combinatorial mutants, we identified that co-culture activates the SaeRS regulatory system in S. aureus, and SaeRS is required for human-specific cytotoxicity. We further discovered that the SaeRS-regulated toxin Panton-Valentine Leukocidin (PVL) drives S. aureus Δagr cytotoxicity following co-culture. We observed similar cytotoxicity phenotypes using clinical isolates of both S. aureus and C. albicans, demonstrating broad conservation of this interaction. Finally, using mice that express the human isoform of the PVL receptor, we found that C. albicans enhances virulence of S. aureus Δagr during co-infection. Overall, this study determined that C. albicans enhances S. aureus toxin-mediated host cell death, and co-culture engages a major virulence regulatory system in a typically non-toxic S. aureus strain to induce potent human-selective cytotoxicity.
    DOI:  https://doi.org/10.1371/journal.ppat.1014490
  3. J Interferon Cytokine Res. 2026 Aug 07. 10799907261473767
    A Distinct c-Raf-MEK1/2-p38 MAPK-Caspase Signaling Pathway Mediates TNF-α-Induced Rapid and Non-Lytic Neutrophil Extracellular Trap Formation in Human Neutrophil-Like Cells.
    Sung-Hun Woo, Yerang Lee, Sung Hoon Kim, Byung Chul Jung, Yoon Suk Kim.
      Neutrophil extracellular traps (NETs) contribute to host defense by trapping pathogens. However, excessive or dysregulated NET formation is implicated in the pathogenesis of various conditions, including thrombosis, autoimmune diseases, and cancer. Despite their clinical significance, the specific intracellular signaling pathways underlying NET formation in response to proinflammatory cytokines, including tumor necrosis factor-α (TNF-α), remain incompletely defined. Thus, in the present study, we aimed to elucidate the mechanisms underlying TNF-α-induced NET formation in human neutrophil-like differentiated HL-60 (dHL-60) cells. TNF-α induced rapid, non-lytic NET formation in dHL-60 cells without compromising cell viability. Mechanistically, TNF-α activated a signaling cascade involving c-Raf, MEK1/2, and p38 mitogen-activated protein kinase (MAPK). This signaling cascade regulated the sequential caspase activation, with caspase-2 acting upstream of caspase-1 cleavage to promote NET formation. Collectively, these findings suggest that TNF-α induces non-lytic NET formation via a defined c-Raf-MEK1/2-p38 MAPK-caspase pathway and a distinct caspase hierarchy. This mechanism offers a valuable experimental model for studying NET-mediated pathologies in proinflammatory environments.
    Keywords:  HL-60; caspase; neutrophil extracellular trap; signaling cascade; tumor necrosis factor-α
    DOI:  https://doi.org/10.1177/10799907261473767
  4. Sci Immunol. 2026 Aug 07. 11(122): eaea0705
    A genotype-first approach reveals the molecular basis of pyrin inflammasome activation.
    Naoya Iwata, Yoshihiko Kuchitsu, Atsushi Hijikata, Hirofumi Shibata, Masahiko Nishitani-Isa, Mariko Aoki, Kazushi Izawa, Hiroyuki Yoshitomi, Junko Takita, Hideki Ueno, Tomohiko Taguchi, Takahiro Yasumi, Yoshitaka Honda.
      Mutations in the MEFV gene, which encodes pyrin, are associated with a spectrum of inflammatory conditions called pyrin-associated autoinflammatory diseases (PAADs). Of the 400 MEFV variants listed in the Infevers database, most are classified as variants of uncertain significance. Thus, genetic diagnosis of PAADs remains challenging, and the molecular mechanisms underlying pyrin activation remain poorly understood. Here, we used a cell-based pyroptosis assay to stratify 265 missense MEFV variants and identified previously uncharacterized pathogenic variants. We then characterized the interaction between the pyrin B30.2 domain and CDC42, a key regulator of pyrin intracellular trafficking and activation. We found that classical familial Mediterranean fever (FMF)-related variants bind tightly to CDC42 to induce pyrin hyperactivation, whereas certain non-FMF variants induce pyrin hyperactivation independently of CDC42, indicating involvement of multiple pathways in pyrin activation. Our approach provides a proof of concept for a genotype-first approach, which may advance our understanding of complex human diseases.
    DOI:  https://doi.org/10.1126/sciimmunol.aea0705
  5. Sci Immunol. 2026 Aug 07. 11(122): eadz8733
    An autoinflammatory CDC42 variant M45L demonstrates the mechanism of pyrin inflammasome activation.
    Shouya Feng, Thomas Reygaerts, Klara Kong, Matthew C Wierzbowski, Dhanya Lakshmi Narayanan, Paul J Baker, Imogen Bishop, Maria Zyulina, Katherine Rosevear, Madeline L Cleveland, Tim C Hewitt, T Daniel Andrews, Davide Randazzo, Peter J Steinbach, Jae Jin Chae, Hyeonji Kim, Daniel L Kastner, William D Renton, Samar Ojaimi, Wonyong Lee, Seth L Masters.
      CDC42 is an evolutionarily conserved guanosine triphosphatase (GTPase) regulating critical cellular and immune processes. Variants in CDC42 therefore cause a spectrum of developmental phenotypes, including hematological and immunological symptoms. Here, we identify a previously unrecognized autoinflammatory condition caused by CDC42Met45→Leu(M45L). We confirm the pathogenicity of CDC42M45L given that it promotes pyrin inflammasome activation, consistent with highly elevated circulating interleukin-18 (IL-18) in all affected individuals. Coimmunoprecipitation demonstrates that CDC42 interacts with the PYD and B30.2 domains of pyrin. The B30.2 interaction is greatly enhanced by CDC42M45L. Models show that CDC42 methionine-45 sits in a hydrophobic cleft of the pyrin B30.2 domain, and substitution with a negatively charged residue prevents colocalization between CDC42 and pyrin. This study supports a model whereby CDC42 nucleates pyrin via the B30.2 domain, after which a threshold is reached to liberate the PYD for inflammasome activation. Blocking the inflammasome-associated cytokine IL-1 was therapeutically effective when tested against this autoinflammatory CDC42M45L endotype.
    DOI:  https://doi.org/10.1126/sciimmunol.adz8733
  6. Sci Immunol. 2026 Aug 07. 11(122): eaea0515
    An N-terminal CDC42 T43I variant reveals the mechanism of pyrin inflammasome activation.
    Mariko Aoki, Alberto Iannuzzo, Philippe Mertz, Shouya Feng, Naoya Iwata, Chiara Perugini, Naomi Tsuchida, Rana El Masri, Yoshihiko Kuchitsu, Rachida Tacine, Simona Coppola, Hirofumi Shibata, Margaux Cescato, Masahiko Nishitani-Isa, Alexandre Terré, Yuri Kawasaki, Sarah Dalmon, Kenichi Nishimura, Flora Magnotti, Satoko Miyatake, Marc André, Keisuke Hamada, Jonathan London, Kazushi Izawa, Akira Niwa, Nobuhiko Okamoto, Kazuhiro Ogata, Masashi Nishikawa, Erika Zara, Megumu K Saito, Marco Tartaglia, Shuichi Ito, Mathieu P Rodero, Koh-Ichi Nagata, Asma Smahi, Naomichi Matsumoto, Laurent Le Corre, Junko Takita, Guilaine Boursier, Atsushi Hijikata, Thomas Henry, Tomohiko Taguchi, Véronique Hentgen, Sophie Georgin-Lavialle, Yoshitaka Honda, Seth L Masters, Takahiro Yasumi, Jérôme Delon.
      Heterozygous carboxyl-terminal variants in the RHO guanosine triphosphatase (GTPase) CDC42 are known to cause severe autoinflammatory syndromes. Here, we identified a heterozygous amino-terminal p.T43I (Thr43→Ile) CDC42 variant in patients with autoinflammation and uncovered a molecular link between CDC42 and the inflammasome sensor pyrin, mutated in the hereditary autoinflammatory syndrome familial Mediterranean fever. We demonstrate that the region surrounding residue T43 of CDC42 interacts with the carboxyl-terminal B30.2 domain of pyrin and regulates its localization and activation. The p.T43I substitution strengthens the CDC42-pyrin interaction through additional van der Waals interactions, leading to increased pyrin inflammasome activation, as evidenced by increased ASC (apoptosis-associated speck-like protein containing a caspase activating and recruitment domain) speck formation, enhanced pyroptosis, and excessive interleukin-1β (IL-1β) and IL-18 production. These findings identify CDC42 as a pyrin ligand and provide critical insights into the role of the pyrin B30.2 domain in inflammasome activation, suggesting dual regulation of pyrin by two RHO family GTPases, RHOA and CDC42.
    DOI:  https://doi.org/10.1126/sciimmunol.aea0515
  7. Proc Natl Acad Sci U S A. 2026 Aug 11. 123(32): e2620143123
    A bacterial fatty acid enzyme hijacks nucleic acid-sensing Toll-like receptor signaling.
    William A Lathram, Priscilla C Lages, Christopher D Radka.
      Innate immune recognition shapes infection outcomes by linking microbial detection to host defense. Although pattern recognition receptors are classified by the ligands they detect (lipids, peptidoglycans, or nucleic acids) cross-talk between these pathways is increasingly recognized. Staphylococcus aureus, a major cause of skin and soft tissue infections, can persist intracellularly, evading immunity and antibiotics. Here, we describe a lipid-based immune evasion strategy in which the S. aureus enzyme oleate hydratase (OhyA) converts host fatty acids into hydroxylated lipids that antagonize TLR3-TRIF-IRF7 signaling, a pathway activated by double-stranded RNA. Deletion of ohyA unleashed this pathway, triggering rapid bacterial clearance, whereas loss of TLR3, TRIF, or IRF7 restored bacterial persistence, establishing a noncanonical antibacterial role for an antiviral signaling pathway. These findings identify a previously unrecognized interface between bacterial lipid metabolism and antiviral immune machinery, highlighting how pathogens manipulate cross-kingdom signaling to evade intracellular immunity.
    Keywords:  Staphylococcus aureus; acute-phase virulence; innate immunity; macrophages; oleate hydratase (OhyA)
    DOI:  https://doi.org/10.1073/pnas.2620143123
  8. Cell Death Dis. 2026 Aug 01. pii: 671. [Epub ahead of print]17(1):
    The anti-tumour activity of TNF in melanoma is determined by cFLIP.
    Johanna Stachelscheid, Cäcilia Kaul, Katrin Gerstenberg, J Paul Werthenbach, Fabian Schorn, Joy Steinkamp, Paola Zigrino, Manolis Pasparakis, Lars M Schiffmann, Hamid Kashkar.
      Tumour necrosis factor (TNF) is a pleiotropic cytokine originally identified for its ability to kill cancer cells. However, a paradoxical tumour-promoting role for TNF emerged when early attempts to exploit its anti-tumour activity in cancer therapy produced conflicting outcomes, raising the question of whether TNF should be viewed as a therapeutic agent or a treatment target in cancer. Here, we demonstrate that expression of cFLIP, a catalytically inactive paralogue of caspase-8 (CASP8), determines the susceptibility of melanoma cells to TNF and thereby controls melanoma growth in a syngeneic, immune-competent mouse model of B16F10 cutaneous melanoma. B16F10 melanoma cells lacking cFLIP (cFlipKO/KO cells) failed to grow in wild-type mice, whereas in TNF-deficient mice, cFlipKO/KO melanoma cells formed palpable tumours and exhibited robust subcutaneous growth. These findings indicate that TNF alone is sufficient to control melanoma growth in the absence of cFLIP. Importantly, the anti-tumour activity of TNF has predominantly been investigated through targeting cellular inhibitors of apoptosis proteins (cIAPs), which promotes RIPK1 activation and TNF-induced cytotoxicity. We show that genomic ablation of cIAPs or RIPK1, in contrast to cFLIP, neither triggered TNF-induced toxicity nor affected melanoma growth in vivo. Collectively, our data underscore the central role of cFLIP in regulating melanoma responses to TNF and suggest that endogenous immune surveillance as well as immunotherapies involving TNF could strongly benefit from cFLIP targeting strategies.
    DOI:  https://doi.org/10.1038/s41419-026-09154-6
  9. Cell Rep. 2026 Aug 04. pii: S2211-1247(26)00849-1. [Epub ahead of print]45(8): 117771
    Circulating cochlin LCCL domain binds to dying cells and enhances efferocytosis.
    Louise Courcol, Ali Hassan, Zofia Haftek-Terreau, Clara Vigneron, Ananga Ghosh, Lucie Collombet, Stefan Tholen, Gaëtan Juban, Anne-Claire Lukaszewicz, Oliver Schilling, Bénédicte F Py, Fabienne Venet.
      Clearance of dead cells by efferocytosis is a critical process for homeostasis, notably by limiting inflammation. Defective efferocytosis has been associated with autoimmune, neurodegenerative, and cardiovascular diseases, as well as chronic infections, making its regulation a potential therapeutic target. Here, we identify circulating cochlin LCCL (Limulus factor C, Cochlin, and Lgl1) domain as a regulator of efferocytosis. Using cell binding assay for recombinant cochlin LCCL domain, we establish its tropism for dead or dying cells of both immune and non-immune lineages from murine and human origins. By three independent functional assays, we demonstrate that endogenous and exogenous cochlin LCCL domain enhances macrophage efferocytosis in vitro and in vivo in lipopolysaccharide (LPS)-induced inflammation and intranasal Pseudomonas aeruginosa infection, to a similar extent as the efferocytosis promoter GAS6. Our findings provide a role of cochlin LCCL domain in the regulation of efferocytosis, alongside its already described pro-inflammatory role, as an immunomodulator for host response and homeostasis.
    Keywords:  CP: cell biology; CP: immunology; LCCL; apoptosis; cochlin; dead cells; efferocytosis; necrosis
    DOI:  https://doi.org/10.1016/j.celrep.2026.117771
  10. EXO. 2026 ;pii: 202613. [Epub ahead of print]1(2):
    Ferroptosis spreading through propagative signals.
    Saloni K Hombalkar, Jyotirekha Das, Michael Overholtzer.
      Ferroptosis is a regulated mechanism of cell death caused by the uncontrolled peroxidation of cellular lipids that has an unusual ability to propagate or spread between cells. Here, we review studies identifying regulators of ferroptosis propagation to consider a working model that might explain this unusual feature. Recent findings implicating the spread of lipid peroxides and iron suggest that these main catalysts of ferroptosis may also be primary vehicles that can spread death between cells. Experiments revealing localized versus long-range effects of propagation are discussed, as well as sensitizing factors that may expand the propagative potential of death induced by Class II ferroptosis-inducing compounds. As ferroptosis propagation may underlie the loss of large groups of cells in degenerative diseases and may also have a specialized role in normal development, consideration of how ferroptosis can spread through propagative signals may be important for understanding both normal tissue dynamics and disease.
    Keywords:  Ferroptosis; erastin; ferritin; glutathione peroxidase 4; iron; lipid peroxidation; lysosome; propagation
    DOI:  https://doi.org/10.70401/EXO.2026.0011
  11. Front Immunol. 2026 ;17 1802300
    IL-33 promotes efferocytosis by peritoneal macrophages by a mechanism associated with rapid granulocyte IL-13 production.
    Stephanie A Legere, Roopa Hebbandi Nanjundappa, Dihia Meghnem, Ian D Haidl, Alexander Edgar, Qianni Hu, Jean-François Légaré, Jean S Marshall.
      Resolution of inflammation is an active process that requires efferocytosis, the engulfment of apoptotic cells by macrophages, mediated by receptors such as MerTK. IL-33 is an alarmin that initiates type 2 immune responses, including increased production of IL-13, which promotes MerTK expression. The ability of IL-33 to promote efferocytosis in vivo was examined. Intraperitoneal administration of IL-33 to mice increased local MerTK+ macrophage numbers within 48h. MerTK+ macrophages were not similarly induced by free mitochondria, an alternative cell damage associated signal. Efferocytotic activity was increased rapidly in response to apoptotic thymocytes in IL-33-treated mice. The established inducer of MerTK expression, IL-13, was detected in peritoneal lavage fluid shortly after IL-33 administration. Peritoneal eosinophils expressed the IL-33 receptor and demonstrated both intracellular IL-13 by flow cytometry and significantly increased Il13 transcript expression following IL-33 treatment. In contrast, neither elevated IL-13 expression nor IL-13 protein secretion was observed in peritoneal lymphocyte populations within the first 6 hours after IL-33 administration. Primary cultures of bone marrow-derived mouse mast cells and eosinophils demonstrated IL-13 protein responses to IL-33 administration within 6 h. Mast cell-deficient Cpa3-Cre; Mcl-1fl/fl mice had significantly reduced IL-13 levels in the peritoneal cavity 3 hours after IL-33 administration when compared with mast cell-containing littermates. In contrast, IL-33-treated eosinophil-deficient ΔdblGATA mice had similar levels of IL-13 at this time point as wild type controls. These data demonstrate that IL-33 promotes MerTK expression, critical for efferocytosis by macrophages, by a process associated with an early rapid local increase in IL-13 production to which mast cells are a substantial early contributor. These findings contribute to our understanding of clinical situations where elevated soluble IL-33 receptor (sST2) and/or lower mast cell numbers are associated with worse clinical outcome.
    Keywords:  MerTK; alarmin cytokine; cytokines; eosinophil; inflammation; inflammation resolution; mast cell; phagocytosis
    DOI:  https://doi.org/10.3389/fimmu.2026.1802300
  12. EMBO J. 2026 Aug 05.
    Damage recognition by intestinal stem cells via Draper promotes adult Drosophila midgut regeneration.
    Martina Legido, Marie Srotyr, Rebecca Wafer, Parthive H Patel.
      Tissue regeneration after injury is crucial for restoring epithelial structure and function. Upon damage, a regenerative microenvironment forms that provides signalling cues that stimulate stem cell proliferation to replace lost cells. While this process is well understood, how stem cells themselves sense damage, translate this input into their proliferation and shape the regenerative microenvironment remains unclear. Here we show that Draper-Src-Shark signalling in Drosophila intestinal stem cells (ISCs) recognises tissue damage by sensing externalised phosphatidylserine on dying midgut epithelial cells and is required for STAT activation in ISCs to promote their proliferation. Unlike its role in phagocytosis, Draper in ISCs does not promote the clearance of these apoptotic enterocytes but rather facilitates ISC proliferation in the presence of damaged enterocytes. Moreover, Draper-Src-Shark signalling in progenitors regulates STAT transcriptional activity in the adjacent visceral muscle, indicating that progenitors can shape the regenerative microenvironment beyond tissue boundaries. As Src and STAT are also activated in the mammalian intestinal epithelium after damage and tumour formation, these findings may help develop therapies for tissue regeneration, inflammatory diseases and cancer.
    DOI:  https://doi.org/10.1038/s44318-026-00890-1
  13. Immunity. 2026 Aug 06. pii: S1074-7613(26)00306-7. [Epub ahead of print]
    Virus-induced deconjugation of ISG15 dysregulates innate immunity and cellular metabolism.
    Junji Zhu, GuanQun Liu, Jielin Xu, Zuberwasim Sayyad, Kun Li, Surajit Chakraborty, Christopher M Goins, Huaxu Yu, Yadi Zhou, Shanti Ross, Evangeline White, Jun Zhao, Oliver Fiehn, Shaun R Stauffer, Feixiong Cheng, Michaela U Gack.
      Interferon-stimulated gene 15 (ISG15) encodes a ubiquitin-like protein that regulates diverse cellular responses, including antiviral immunity, through its conjugation to proteins in a process known as ISGylation. Several pathogens, including SARS-CoV-2, subvert ISGylation by encoding deISGylating enzymes. However, the direct targets and physiological consequences of coronaviral deISGylation remain poorly defined. Here, we genetically ablated the deISGylating activity of the SARS-CoV-2-encoded papain-like protease (PLpro) and found that loss of deISGylation boosted innate immune activation, attenuated viral replication, and promoted viral clearance in human cells and mice. Metabolomics, ISGylome proteomics, and functional analyses revealed that PLpro deISGylation relieved metabolic restriction of virus infection by directly regulating the activity of key enzymes controlling glycolysis, the pentose phosphate pathway, and redox homeostasis. These findings provide fundamental insight into how reversible ISGylation regulates immunity and metabolic processes at the molecular level and highlight viral deISGylation as a major strategy to overcome host immunometabolic defenses.
    Keywords:  ISG15; ISGylation; PLpro; SARS-CoV-2; innate immunity; interferon; metabolism
    DOI:  https://doi.org/10.1016/j.immuni.2026.07.007
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