bims-cediti Biomed News
on Cell death in innate immunity, inflammation, and tissue repair
Issue of 2025–06–01
twenty-one papers selected by
Kateryna Shkarina, Universität Bonn
  1. ATP8B1 regulates PIP2 localization and cleavage of pyroptotic executioner Gasdermin D.
  2. PDE10A Inhibition Reduces NLRP3 Activation and Pyroptosis in Sepsis and Nerve Injury.
  3. Evolutionary and functional analyses reveal a role for the RHIM in tuning RIPK3 activity across vertebrates.
  4. Clustering of NLRP3 induced by membrane or protein scaffolds promotes inflammasome assembly.
  5. SARM1: a key multifaceted component in immunoregulation, inflammation and neurodegeneration.
  6. The histone demethylase Kdm5 controls Hid-induced cell death in Drosophila.
  7. Helicobacter pylori delays neutrophil apoptosis but also drives the formation of cells with a leaky plasma membrane: Implications for inflammation.
  8. Shikonin inhibits NLRP3 inflammasome activation and controls inflammatory disease.
  9. Extracellular vesicles from diverse fungal pathogens induce species-specific and endocytosis-dependent immunomodulation.
  10. Gasdermin D drives the systemic storm and mortality after trauma with hemorrhage to a greater degree in biological females than males.
  11. KSHV miRNAs target STING to evade innate immunity and facilitate KSHV lytic reactivation from latency.
  12. Metformin-Induced Apoptosis Is Mediated Through Mitochondrial VDAC1.
  13. Macrophage extracellular traps as key mediators of scleral remodeling in myopia induced by hypoxia and activated platelets.
  14. Tegavivint triggers TECR-dependent nonapoptotic cancer cell death.
  15. ExSPECKt the unexpected: NLRP3-caspase-8-dependent cell death in RBCs.
  16. Inhibition of mitochondrial protein import and proteostasis by a pro-apoptotic lipid.
  17. A viral necrosome mediates direct RIPK3 activation to promote inflammatory necroptosis.
  18. NOD2-NLRP3 Axis and Asthma.
  19. Tipping the balance: innate and adaptive immunity in mitochondrial disease.
  20. Alternative cGAS signaling promotes herpes simplex encephalitis.
  21. Mast cells activated in vitro can modulate macrophage polarization and antibacterial responses.
  1. Proc Natl Acad Sci U S A. 2025 Jun 03. 122(22): e2502798122
    ATP8B1 regulates PIP2 localization and cleavage of pyroptotic executioner Gasdermin D.
    Nilam Bhandari, Ashutosh Prince, Mariam R Khan, C Alicia Traughber, Kalash Neupane, Shuhui W Lorkowski, Gregory Brubaker, Elif G Ertugral, Chandrasekhar R Kothapalli, George R Dubyak, Jonathan D Smith, Kailash Gulshan.
      Mutations in ATP8B1 cause progressive familial intrahepatic cholestasis, with symptoms including pruritus, pancreatitis, fat malabsorption, intestinal inflammation, and failure to thrive. High-throughput studies showed interconnection between ATP8B1 and phosphoinositide (PIPs), but the mechanism linking ATP8B1, lipid metabolism, and inflammation remains unclear. Atp8b1G308V/G308V mouse model, unbiased RNAseq, high-resolution-stimulation emission depltion (STED)-microscopy, and Crispr-Cas9 generated ATP8B1-/- knockouts in hepatocytes/monocytes/macrophages were used to determine role of ATP8B1 in phosphatidylinositol,4-5-bisphosphate (PIP2) trafficking and inflammation. Human ATP8B1, purified from Sf9 insect cells and reconstituted in proteoliposomes, was used to test cell-free PIP2 flip. Various in-vitro techniques were used for testing direct interaction between PIP2 and ATP8B1. ATP8B1 maintains PIP2 at the inner leaflet of plasma membrane (PM). ATP8B1 flips PIP2 in cells, without altering flip of PE or bulk-endocytosis. ATP8b1 flips PIP2 in a cell-free system. ATP8B1 deletion promotes bile-salt-mediated cholesterol extraction from hepatocytes in a PIP2-dependent manner. PIP2 directly binds to the P-loop of ATP8B1. Unbiased RNAseq showed upregulation of inflammatory cytokines in ATP8b1-/- immune cells. ATP8B1-/- monocytes/macrophages showed aberrant lipopolysaccharide (LPS)-induced cleavage of GSDMD, formation of GSDMD pores, and interleukin-1beta (IL1β) release. Inflammation-resolving efferocytosis was impaired in ATP8B1-/- macrophages. Biophysical properties of PM were altered in ATP8b1-/- cells, with the mechanism being disrupted localization of PIP2. Atp8b1G308V/G308V mice exposed to LPS showed higher plasma IL1β and lower survival rates vs. WT mice. ATP8B1 maintains PIP2 at the inner leaflet of PM. ATP8b1 directly flips and binds PIP2. ATP8B1 regulates LPS-induced GsdmD cleavage, formation of GsdmD pores, IL1β release, and mortality in mice.
    Keywords:  ATP8b1; Gasdermin D; PFIC1; PIP2; inflammasome
    DOI:  https://doi.org/10.1073/pnas.2502798122
  2. Int J Mol Sci. 2025 May 08. pii: 4498. [Epub ahead of print]26(10):
    PDE10A Inhibition Reduces NLRP3 Activation and Pyroptosis in Sepsis and Nerve Injury.
    Bradford C Berk, Camila Lage Chávez, Chia George Hsu.
      Cell death and inflammation are key innate immune responses, but excessive activation can cause tissue damage. The NLRP3 inflammasome is a promising target for reducing inflammation and promoting recovery. Immunometabolism regulates NLRP3 responses in neurological and inflammatory diseases through cyclic nucleotide signaling. Targeting phosphodiesterases (PDEs), which hydrolyze cAMP and cGMP, offer a novel approach to mitigate inflammation. While 14 PDE inhibitors are FDA-approved, PDE10A's role in NLRP3 inflammasome activation remains unclear. This study investigates the effects of PDE10A inhibition on inflammasome-driven inflammation using two PDE10A inhibitors, MP-10 and TP-10, in macrophage and animal models of sepsis and traumatic nerve injury. Our results show that PDE10A inhibition reduces inflammasome activation by preventing ASC speck formation and by lowering levels of cleaved caspase-1, gasdermin D, and IL-1β, which are key mediators of pyroptosis. In the sepsis model, MP-10 significantly reduced inflammation, decreased plasma IL-1β, alleviated thrombocytopenia, and improved organ damage markers. In the nerve injury model, PDE10A inhibition enhanced motor function recovery and reduced muscle atrophy-related gene expression. These findings suggest that PDE10A inhibition could be a promising therapeutic approach for inflammatory and neuromuscular injuries. Given MP-10's established safety in human trials, Phase 2 clinical studies for sepsis and nerve injury are highly promising.
    Keywords:  NLRP3 inflammasome; macrophage; nerve injury; phosphodiesterase 10A; sepsis
    DOI:  https://doi.org/10.3390/ijms26104498
  3. Elife. 2025 May 28. pii: RP102301. [Epub ahead of print]13
    Evolutionary and functional analyses reveal a role for the RHIM in tuning RIPK3 activity across vertebrates.
    Elizabeth J Fay, Kolya Isterabadi, Charles M Rezanka, Jessica Le, Matthew D Daugherty.
      Receptor interacting protein kinases (RIPK) RIPK1 and RIPK3 play important roles in diverse innate immune pathways. Despite this, some RIPK1/3-associated proteins are absent in specific vertebrate lineages, suggesting that some RIPK1/3 functions are conserved, while others are more evolutionarily labile. Here, we perform comparative evolutionary analyses of RIPK1-5 and associated proteins in vertebrates to identify lineage-specific rapid evolution of RIPK3 and RIPK1 and recurrent loss of RIPK3-associated proteins. Despite this, diverse vertebrate RIPK3 proteins are able to activate NF-κB and cell death in human cells. Additional analyses revealed a striking conservation of the RIP homotypic interaction motif (RHIM) in RIPK3, as well as other human RHIM-containing proteins. Interestingly, diversity in the RIPK3 RHIM can tune activation of NF-κB while retaining the ability to activate cell death. Altogether, these data suggest that NF-κB activation is a core, conserved function of RIPK3, and the RHIM can tailor RIPK3 function to specific needs within and between species.
    Keywords:  NF-kB; RIP kinases; evolutionary biology; human; immunology; inflammation; innate immunity; vertebrate evolution
    DOI:  https://doi.org/10.7554/eLife.102301
  4. Nat Commun. 2025 May 27. 16(1): 4887
    Clustering of NLRP3 induced by membrane or protein scaffolds promotes inflammasome assembly.
    Elvira Boršić, Taja Železnik Ramuta, Sara Orehek, Mateja Erdani Kreft, Matthias Geyer, Roman Jerala, Iva Hafner-Bratkovič.
      NLRP3 is a pattern recognition receptor forming an inflammasome in response to diverse pathogen and self-derived triggers, but molecular insights on NLRP3 activation are still lacking. Here, we drive ectopic NLRP3 to different subcellular locations in NLRP3-deficient macrophages to map the spatial activation profile of NLRP3, and find that NLRP3 variants enriched at the organellar membranes respond to canonical triggers similarly to wild-type NLRP3; however, unlike wild-type, these NLRP3 variants can be activated even in the absence of the polybasic phospholipid-binding segment. Mechanistically, membrane or protein scaffolds mediate NLRP3 clustering, which leads to the unfastening of the inactive NACHT domain conformation preceding the activated NLRP3 oligomer formation. Our data thus suggest that scaffold-promoted clustering is an important step in NLRP3 activation, enabling NLRP3 to sense distinct activator-induced cellular anomalies exhibited via lipid or protein assemblies, thereby establishing NLRP3 as the master sensor of perturbations in cell homeostasis.
    DOI:  https://doi.org/10.1038/s41467-025-60277-4
  5. Front Immunol. 2025 ;16 1521364
    SARM1: a key multifaceted component in immunoregulation, inflammation and neurodegeneration.
    Samuel Dos Santos Oliveira, João Vinícius Honório da Silva, Raquel de Souza Vieira, Luís Felipe Serra Moreira, Pedro Henrique Araújo Bandeira, Beatriz Leocata Ramos, Marco Antônio Ataíde Silva, Niels Olsen Saraiva Câmara.
      The downstream signaling pathways of TLR activation involve a family of adaptor proteins, including MYD88, TIRAP, TRIF, TRAM, and SARM1. The first four proteins stimulate inflammatory and antiviral responses, playing crucial roles in innate immunity against various pathogens. In contrast, SARM1 promotes immunity to microorganisms in invertebrate animals independently of TLRs, and negatively regulates inflammatory responses in metazoan organisms. SARM1 inhibits TRIF, reduces the activation of various inflammasomes, and induces mitochondrial damage and cell death to eliminate hyperactivated cells. This regulation is essential to ensure timely control of immune responses and to prevent excessive inflammation. Recently, it was discovered that SARM1 can hydrolyze NAD, a critical component of cellular metabolism. The reduction of NAD levels by SARM1 is linked to the progression of Wallerian degeneration following neuronal injury and may also play a role in the immunoregulation of lymphoid and myeloid cells. Since SARM1 can be pharmacologically modulated, it presents promising opportunities for developing treatments for inflammatory and neurodegenerative diseases.
    Keywords:  cell death; immunometabolism; immunoregulation; innate immunity; neurodegenerative disease
    DOI:  https://doi.org/10.3389/fimmu.2025.1521364
  6. Front Cell Death. 2024 ;pii: 1471050. [Epub ahead of print]3
    The histone demethylase Kdm5 controls Hid-induced cell death in Drosophila.
    Hans-Martin Herz, Andreas Bergmann.
      We conducted an EMS mutagenesis screen on chromosome arm 2L to identify recessive suppressors of GMR-hid-induced apoptosis in the Drosophila eye. Through this screen, we recovered three alleles of the lysine demethylase gene Kdm5. Kdm5, a member of the JmjC-domain-containing protein family, possesses histone demethylase activity towards H3K4me3. Our data suggest that Kdm5 specifically regulates Hid-induced cell death during development, as we did not observe control of Reaper- or Grim-induced cell death by Kdm5. Interestingly, GMR-hid-induced apoptosis is suppressed independently of Kdm5's demethylase activity. Our findings indicate that Rbf and dMyc are necessary for Kdm5 mosaics to suppress GMR-hid-induced cell death. Moreover, Kdm5 mosaics failed to suppress apoptosis induced by a mutant form of Hid that is resistant to inhibition by Erk-type MAPK activity. Additionally, Kdm5 dominantly enhances the wing phenotype of an activated MAPK mutant. These results collectively suggest that Kdm5 controls Hid-induced apoptosis by regulating the Rbf, dMyc, and MAPK pathways.
    Keywords:  Drosophila; Hid; Kdm5; MAPK; Myc; Rb; cell death
    DOI:  https://doi.org/10.3389/fceld.2024.1471050
  7. Mol Immunol. 2025 May 23. pii: S0161-5890(25)00126-9. [Epub ahead of print]183 236-245
    Helicobacter pylori delays neutrophil apoptosis but also drives the formation of cells with a leaky plasma membrane: Implications for inflammation.
    Tran Duong Thai, Chatcharin Kamsom, Wisitsak Phoksawat, Arnone Nithichanon, Kiatichai Faksri, Banchob Sripa, Steven W Edwards, Kanin Salao.
      Opisthorchis viverrini (OV)-induced cholangiocarcinoma (CCA) is a significant public health concern in countries in the Lower Mekong Basin. OV is a reservoir for Helicobacter pylori (H. pylori), and so many individuals are co-infected with these two biological carcinogens. Our study aimed to investigate interactions between H. pylori isogenic strains possessing or lacking the pathogenicity factor CagA (cagA+ and cagA-) with neutrophils. Both H. pylori strains were co-cultured with neutrophils in vitro, and neutrophil activation, phagocytosis, reactive oxygen species (ROS) production, and cell survival/apoptosis were measured. Both isogenic strains of H. pylori stimulated phagocytosis and while the cagA- strain induced slightly higher ROS production, both strains served as potent activators of neutrophils. Notably, H. pylori induced rapid cell death in a sub-population of neutrophils after 30 min of co-incubation while extending the lifespan of the neutrophils that survived this initial cell death. This initial incubation resulted in the appearance of propidium iodide (PI)+ neutrophils, i.e. cells with a compromised plasma membrane that could result in the release of inflammation-promoting neutrophil contents. While significantly more viable neutrophils were detected after 24 h (and 48 h) incubation with H. pylori, those cells that did not survive also showed characteristics of a compromised plasma membrane (i.e. PI+). We propose that the combinations of PI+ neutrophils with leaky plasma membranes and non-apoptotic neutrophils with enhanced survival after incubation with H. pylori may drive persistent inflammation. These findings offer new insights into the immunopathogenesis of OV and H. pylori co-infections, which may help improve OV treatment strategies.
    Keywords:  Apoptosis; Helicobacter pylori; Neutrophils; Opisthorchis viverrini; cagA
    DOI:  https://doi.org/10.1016/j.molimm.2025.05.006
  8. Sci Rep. 2025 May 30. 15(1): 19037
    Shikonin inhibits NLRP3 inflammasome activation and controls inflammatory disease.
    Jing Huang, Mengmeng Dai, Xinyu Huang, Wenqing Qi, Jing Jing, Jiayi He, Zhizhuo Lu, Chaofang Zhang, Guiling Wang, Yuanfang Ma, Hailong Zhang, Run Cao.
      Shikonin (SHK) is a plant-derived naphthoquinone known for its anti-inflammatory activity, though the mechanism remains largely unexplored. The NLRP3 inflammasome, one of the most studied inflammasomes, can cause uncontrolled inflammation and drive various diseases when dysregulated. Here, we confirmed that SHK specifically abolished NLRP3 inflammasome activation by suppressing caspase-1 maturation and the secretion of IL-1β and IL-18. Our data demonstrated that SHK disrupted NLRP3 inflammasome assembly, primarily by blocking NLRP3 and ASC binding, thereby preventing ASC oligomerization and ASC speck formation. Furthermore, SHK reduced reactive oxygen species (ROS) production, inhibiting the generation of oxidized mitochondrial DNA (ox-mtDNA), a known inducer of NLRP3 inflammasome activation. In vivo, we showed that SHK's anti-inflammatory effect in DSS-induced ulcerative colitis (UC) and LPS-induced systemic inflammation associated with the reduction of NLRP3 inflammasome activation, as confirmed by decreased IL-1β and IL-18 release. This paper reveals the mechanism through which SHK inhibits inflammation and provides a potentially effective pharmacological strategy for treating NLRP3-related diseases.
    Keywords:  Inflammatory diseases; NLRP3inflammasome; ROS; SHK; ox-mtDNA
    DOI:  https://doi.org/10.1038/s41598-025-03512-8
  9. PLoS Pathog. 2025 May 30. 21(5): e1012879
    Extracellular vesicles from diverse fungal pathogens induce species-specific and endocytosis-dependent immunomodulation.
    Geneva N Kwaku, Kirstine Nolling Jensen, Patricia Simaku, Daniel J Floyd, Joseph W Saelens, Christopher M Reardon, Rebecca A Ward, Kyle J Basham, Olivia W Hepworth, Tammy D Vyas, Daniel Zamith-Miranda, Joshua D Nosanchuk, Jatin M Vyas, Hannah Brown Harding.
      Microbial pathogens generate extracellular vesicles (EVs) for intercellular communication and quorum sensing. Microbial EVs also induce inflammatory pathways within host innate immune cells. We previously demonstrated that EVs secreted by Candida albicans trigger type I interferon signaling in host cells specifically via the cGAS-STING innate immune signaling pathway. Here, we show that despite sharing similar properties of morphology and internal DNA content, the interactions between EVs and the innate immune system differ according to the parental fungal species. EVs secreted by C. albicans, Saccharomyces cerevisiae, Cryptococcus neoformans, and Aspergillus fumigatus are differentially endocytosed by murine macrophages triggering varied cytokine responses, innate immune signaling, and subsequent immune cell recruitment. Notably, polysaccharide and hydrophobic protein structures on the outer layers of C. neoformans and A. fumigatus EVs inhibit efficient internalization by macrophages and dampen innate immune activation. Our data uncover the functional consequences of the internalization of diverse fungal EVs by immune cells and reveal novel insights into the early innate immune response to distinct clinically significant fungal pathogens.
    DOI:  https://doi.org/10.1371/journal.ppat.1012879
  10. Sci Transl Med. 2025 May 28. 17(800): eado2622
    Gasdermin D drives the systemic storm and mortality after trauma with hemorrhage to a greater degree in biological females than males.
    Xuejing Sun, Sultan S Abdelhamid, Zachary Secunda, Robert Voinchet, Alyssa Gregory, Jacob Scioscia, Mehves Ozel, Jennifer L Darby, Hamed Moheimani, Qing-De Wang, Jishnu Das, Matthew D Neal, Upendra K Kar, Jason L Sperry, Timothy R Billiar.
      Severe injury accompanied by hemorrhagic shock triggers an early release of cell constituents into the circulation, referred to as the systemic storm. The systemic storm drives the systemic inflammatory response and is associated with increased mortality. The role of programmed cell death (PCD) in the systemic storm was investigated in mice that underwent hemorrhagic shock with tissue trauma (HS/T) followed by crystalloid resuscitation. Wild-type (WT) mice were treated with inhibitors, including z-VAD, necrostatin-1, ferrostatin-1, or disulfiram (DSF), to block the different forms of PCD. Gasdermin D (GSDMD)-dependent PCD was further targeted using Gsdmd-/- mice. Untargeted metabolomics and proteomics were used as the primary end point to gain a comprehensive view of the composition changes in the circulation. Although all inhibitor strategies partially reversed the systemic storm, the largest reversal occurred in Gsdmd-/- mice and WT mice treated with DSF, a nonspecific inhibitor of GSDMD pore formation. Weighted correlation network analysis and machine learning identified a subset of omics features increased in the circulation in a GSDMD-dependent manner. Linear regression analysis using a GSDMD-specific omics score (GSOS) in a published multiomic dataset from patients with trauma showed correlation of the GSOS with outcomes and inflammation. Female sex emerged as the variable with the strongest relationship to the GSOS in injured humans, a finding confirmed in mice. Last, DSF treatment or GSDMD deletion led to improvement in blood pressure recovery and increased survival in both sexes. These protective effects of DSF were observed when administered after HS/T, underscoring its potential as a therapeutic intervention.
    DOI:  https://doi.org/10.1126/scitranslmed.ado2622
  11. Cell Rep. 2025 May 24. pii: S2211-1247(25)00512-1. [Epub ahead of print]44(6): 115741
    KSHV miRNAs target STING to evade innate immunity and facilitate KSHV lytic reactivation from latency.
    Kimberly Paulsen, Rosenna Chan, Lauren Gay, Zhe Ma.
      Kaposi sarcoma-associated herpesvirus (KSHV) employs various strategies to evade host immune surveillance and maintain lifelong latency. The cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) DNA sensing pathway is a key innate immunity pathway that detects viral DNA and restricts KSHV lytic replication upon reactivation from latency. Here, we identify three KSHV microRNAs (miRNAs), miR-K12-6-3p, miR-K12-7-3p, and miR-K12-11-3p, that directly bind to STING1 mRNA to repress its translation and inhibit downstream immune signaling. Exogenous delivery of these KSHV miRNAs led to decreased STING expression and attenuated cGAS/STING signaling in response to STING agonist stimulation. Conversely, genetic deletion of these KSHV miRNAs rescued STING and interferon-stimulated gene expression in latent KSHV cell lines, delaying KSHV lytic reactivation and reducing KSHV lytic gene expression. These findings shed light on the immune evasion strategy of KSHV miRNA-mediated STING repression, representing the discovery of viral miRNAs that target STING.
    Keywords:  CP: Immunology; KSHV; STING; innate immunity; latency; lytic reactivation; miRNA
    DOI:  https://doi.org/10.1016/j.celrep.2025.115741
  12. Pharmaceuticals (Basel). 2025 May 20. pii: 757. [Epub ahead of print]18(5):
    Metformin-Induced Apoptosis Is Mediated Through Mitochondrial VDAC1.
    Anna Shteinfer-Kuzmine, Meital M Moyal, Aditya Karunanithi Nivedita, Sweta Trishna, Almog Nadir, Shubhandra Tripathi, Varda Shoshan-Barmatz.
      Background: Besides diabetes mellitus, metformin has been identified as a potential therapeutic agent for treating various other conditions that include various cancers, cardiovascular diseases, neurodegenerative diseases, and aging. In cancer, metformin increased apoptotic cell death, while inhibiting it in neurodegenerative diseases. Thus, different modes of metformin action at the molecular level have been proposed. Methods: In this study, we present the mitochondria and the VDAC1 (voltage-dependent anion channel) as a potential target of metformin. Results: Metformin induces VDAC1 overexpression, its oligomerization, and subsequent apoptosis. Metformin analogs phenformin and buformin at much lower concentrations also induce VDAC1 overexpression, oligomerization, and cell death. We demonstrate the interaction of metformin with purified VDAC1, which inhibited its channel conduction in a voltage-dependent manner. Metformin bound to the synthetic VDAC1-N-terminal peptide and binding to this domain was also found by its molecular docking with VDAC1. Moreover, we demonstrated metformin binding to purified hexokinases (HK-I) with a 400-fold lower metformin concentration than that required for cell death induction. In cells, metformin induced HK-I detachment from the mitochondrial VDAC1. Lastly, metformin increased the expression of NLRP3 and ASC and induced their co-localization, suggesting inflammasome activation. Conclusions: The results suggest that VDAC1 is a target for metformin and its analogs, and this is associated with metformin's adverse effects on many diseases.
    Keywords:  VDAC1; apoptosis; hexokinase; metformin; mitochondria
    DOI:  https://doi.org/10.3390/ph18050757
  13. Cell Rep. 2025 May 28. pii: S2211-1247(25)00542-X. [Epub ahead of print]44(6): 115771
    Macrophage extracellular traps as key mediators of scleral remodeling in myopia induced by hypoxia and activated platelets.
    Qianhong Feng, Jiayue Yuan, Yingying Hu, Chenli Feng, Xinguang Lin, Shichu Liu, Shunmei Ji, Xiuyu Mao, Xueqi Lin, Jing Cong, Xianglian Li, Xinran Li, Hao Li, Dapeng Yan, Jinhui Dai.
      High myopia poses a significant public health challenge due to its rising prevalence and the associated risk of vision-threatening complications. Macrophages play a crucial role in myopic changes; however, the underlying mechanisms remain poorly understood. In the present work, we utilized a mouse lens-induced myopia (LIM) model to elucidate the role of macrophages in myopic scleral remodeling through the release of macrophage extracellular traps (METs). Inhibition of scleral MET release, either through genetic knockout or the MET release inhibitor lactoferrin, effectively suppressed LIM-induced myopia progression. We further investigated the factors that trigger MET release in myopic sclera. Our findings demonstrated that scleral hypoxia, in conjunction with hypoxia-activated platelets, induced autophagy in macrophages, leading to the subsequent release of METs. These findings identify a significant therapeutic target for myopia management and suggest lactoferrin as a promising pharmacological candidate for myopia prevention.
    Keywords:  CP: Immunology; autophagy; extracellular traps; fibroblasts; hypoxia; lactoferrin; macrophages; myopia; platelets; sclera; scleral remodeling
    DOI:  https://doi.org/10.1016/j.celrep.2025.115771
  14. Nat Chem Biol. 2025 May 26.
    Tegavivint triggers TECR-dependent nonapoptotic cancer cell death.
    Logan Leak, Ziwei Wang, Alby J Joseph, Brianna Johnson, Alyssa A Chan, Cassandra M Decosto, Leslie Magtanong, Pin-Joe Ko, Weaverly Colleen Lee, Joan Ritho, Sophia Manukian, Alec Millner, Shweta Chitkara, Jennifer J Salinas, Rachid Skouta, Matthew G Rees, Melissa M Ronan, Jennifer A Roth, Chad L Myers, Jason Moffat, Charles Boone, Steven J Bensinger, David A Nathanson, G Ekin Atilla-Gokcumen, Everett J Moding, Scott J Dixon.
      Small molecules that induce nonapoptotic cell death are of fundamental mechanistic interest and may be useful to treat certain cancers. Here we report that tegavivint, a drug candidate undergoing human clinical trials, can activate a unique mechanism of nonapoptotic cell death in sarcomas and other cancer cells. This lethal mechanism is distinct from ferroptosis, necroptosis and pyroptosis and requires the lipid metabolic enzyme trans-2,3-enoyl-CoA reductase (TECR). TECR is canonically involved in the synthesis of very-long-chain fatty acids but appears to promote nonapoptotic cell death in response to CIL56 and tegavivint via the synthesis of the saturated long-chain fatty acid palmitate. These findings outline a lipid-dependent nonapoptotic cell death mechanism that can be induced by a drug candidate currently being tested in humans.
    DOI:  https://doi.org/10.1038/s41589-025-01913-4
  15. Cell. 2025 May 29. pii: S0092-8674(25)00503-3. [Epub ahead of print]188(11): 2833-2835
    ExSPECKt the unexpected: NLRP3-caspase-8-dependent cell death in RBCs.
    Rebecca E Tweedell, Thirumala-Devi Kanneganti.
      Red blood cell (RBC) lysis can cause morbidity and mortality. However, the molecular mechanisms underlying RBC lysis are not fully characterized, limiting therapeutic options. In this issue of Cell, Chen et al. identify a crucial role for the NLRP3-ASC-caspase-8 complex in driving programmed lytic cell death in RBCs.
    DOI:  https://doi.org/10.1016/j.cell.2025.04.033
  16. Elife. 2025 May 30. pii: RP93621. [Epub ahead of print]13
    Inhibition of mitochondrial protein import and proteostasis by a pro-apoptotic lipid.
    Josep Fita-Torró, José Luis Garrido-Huarte, Lucía López-Gil, Agnès H Michel, Benoit Kornmann, Amparo Pascual-Ahuir, Markus Proft.
      Mitochondria-mediated cell death is critically regulated by bioactive lipids derived from sphingolipid metabolism. The lipid aldehyde trans-2-hexadecenal (t-2-hex) induces mitochondrial dysfunction from yeast to humans. Here, we apply unbiased transcriptomic, functional genomics, and chemoproteomic approaches in the yeast model to uncover the principal mechanisms and biological targets underlying this lipid-induced mitochondrial inhibition. We find that loss of Hfd1 fatty aldehyde dehydrogenase function efficiently sensitizes cells for t-2-hex inhibition and apoptotic cell death. Excess of t-2-hex causes a profound transcriptomic response with characteristic hallmarks of impaired mitochondrial protein import, like activation of mitochondrial and cytosolic chaperones or proteasomal function and severe repression of translation. We confirm that t-2-hex stress induces rapid accumulation of mitochondrial pre-proteins and protein aggregates and subsequent activation of Hsf1- and Rpn4-dependent gene expression. By saturated transposon mutagenesis, we find that t-2-hex tolerance requires an efficient heat shock response and specific mitochondrial and ER functions and that mutations in ribosome, protein, and amino acid biogenesis are beneficial upon t-2-hex stress. We further show that genetic and pharmacological inhibition of protein translation causes t-2-hex resistance, indicating that loss of proteostasis is the predominant consequence of the pro-apoptotic lipid. Several TOM subunits, including the central Tom40 channel, are lipidated by t-2-hex in vitro and mutation of accessory subunits Tom20 or Tom70 confers t-2-hex tolerance. Moreover, the Hfd1 gene dose determines the strength of t-2-hex mediated inhibition of mitochondrial protein import, and Hfd1 co-purifies with Tom70. Our results indicate that the transport of mitochondrial precursor proteins through the outer mitochondrial membrane is sensitively inhibited by the pro-apoptotic lipid and thus represents a hotspot for pro- and anti-apoptotic signaling.
    Keywords:  S. cerevisiae; apoptosis; biochemistry; chemical biology; genetics; genomics; lipid signaling; mitochondrial protein import; proteostasis; sphingolipid metabolism; yeast
    DOI:  https://doi.org/10.7554/eLife.93621
  17. Proc Natl Acad Sci U S A. 2025 Jun 03. 122(22): e2420245122
    A viral necrosome mediates direct RIPK3 activation to promote inflammatory necroptosis.
    Shufen Li, Hao Li, Zhenxing Zhou, Meidi Ye, Yifei Wang, Wenqin Li, Zhenqiong Guan, Zihan Guan, Chongtao Zhang, Yulan Zhang, Wei Liu, Ke Peng.
      Necroptosis is an inflammatory programmed cell death pathway triggered by RIPK3 activation through one of the upstream RHIM-domain-containing proteins including RIPK1, TRIF, and ZBP1. Whether necroptosis can be activated independent of the upstream signaling pathways leading to inflammatory pathogenesis remains ambiguous. Here, we revealed a mechanism in which a viral protein mediates direct RIPK3 activation resulting in severe inflammatory pathogenesis in patients. The nonstructural protein NSs of a pathogenic hemorrhagic virus, SFTSV, interacts with the RIPK3 kinase domain and forms biocondensate to promote RIPK3 autophosphorylation and necroptosis activation in an RHIM-independent manner. In parallel, sequestration of RIPK3 within the NSs-RIPK3 condensate inhibited RIPK3-mediated apoptosis and promoted viral replication. Infection with an SFTSV NSs mutant virus not forming NSs condensate triggered pronounced apoptosis resulting in reduced viral replication and decreased fatality in vivo. Blocking SFTSV-triggered necroptosis through depletion of MLKL or treatment with a RIPK3-kinase inhibitor reduced viral inflammatory pathogenesis and fatality in vivo. In contrast, blocking SFTSV-triggered apoptosis through depletion of RIPK3 resulted in enhanced viral replication and increased fatality in vivo. The virus-triggered necroptosis correlated with severe inflammatory pathogenesis and lethality in virus-infected patients. The NSs-RIPK3 condensate may represent a necroptosis activation mechanism that promotes viral pathogenesis.
    Keywords:  NSs; RIPK3; cell death; inflammatory pathogenesis; viral necrosome
    DOI:  https://doi.org/10.1073/pnas.2420245122
  18. J Asthma Allergy. 2025 ;18 769-777
    NOD2-NLRP3 Axis and Asthma.
    Xulong Cai.
      Patients with asthma frequently experience recurrent symptoms including coughing, wheezing, shortness of breath, and chest tightness. Asthma is a common public health concern. It is characterized by chronic airway inflammation. However, The pathogenesis of asthma is complex. Inflammasomes are signaling platforms that regulate the inflammatory response. There is a correlation between inflammasomes and asthma. Pattern recognition receptors recognize danger signals and participate in inflammasome activation. Nucleotide-binding and oligomerization domain-containing 2 (NOD2), a pattern recognition receptor, senses microbial components and triggers immune responses. There have been studies showing a correlation between NOD2 and asthma. The nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) participates in the formation of inflammasomes. NLRP3 are involved in asthma pathogenesis. In this review, we discuss the roles of NOD2 and NLRP3 in the pathogenesis of asthma.
    Keywords:  NLRP3; NOD2; asthma; inflammasome
    DOI:  https://doi.org/10.2147/JAA.S526788
  19. Curr Opin Immunol. 2025 May 26. pii: S0952-7915(25)00042-1. [Epub ahead of print]95 102566
    Tipping the balance: innate and adaptive immunity in mitochondrial disease.
    Andrew Phillip West, Peter J McGuire.
      Mitochondrial diseases (MtD) provide a unique window into the complex interplay between metabolism and immune function. These rare disorders, caused by defects in oxidative phosphorylation, result in bioenergetic deficiencies that disrupt multiple organ systems. While traditionally studied for their metabolic impact, MtD also profoundly affect the immune system, altering both innate and adaptive responses. This review explores how mitochondrial dysfunction shapes immune dysregulation, influencing thymocyte maturation, regulatory T cells, and B cell function while also driving innate immune activation through mitochondrial DNA instability and type I interferon signaling. Additionally, MtD highlight an emerging overlap between inborn errors of metabolism and inborn errors of immunity, revealing shared pathways that connect mitochondrial dysfunction to immune deficiencies and inflammatory disease. Studying MtD not only advances our understanding of immunometabolism but also provides critical insights into more common inflammatory and autoimmune conditions, offering potential therapeutic targets that extend beyond rare mitochondrial disorders.
    DOI:  https://doi.org/10.1016/j.coi.2025.102566
  20. Proc Natl Acad Sci U S A. 2025 Jun 03. 122(22): e2423873122
    Alternative cGAS signaling promotes herpes simplex encephalitis.
    Liraz Shmuel-Galia, Zhaozhao Jiang, Laurel Stine, Sara Cahill, Sze-Ling Ng, Ruth Wilson, Richard Kumaran Kandasamy, Evelyn A Kurt-Jones, Joshi M Ramanjulu, John Bertin, Viera Kasparcova, G Scott Pesiridis, Katherine A Fitzgerald, Fiachra Humphries.
      During infection, foreign DNA is sensed by cyclic GMP-AMP synthase (cGAS) leading to the production of cGAMP, STING-dependent type I interferon and proinflammatory cytokine expression, and autophagy. To prevent a response to self-DNA, cGAS activity is tightly regulated. Dysregulation of cGAS underpins interferonopathies, such as Aicardi-Goutières syndrome, as well as Lupus and neurodegenerative diseases like Parkinson's disease. Thus, cGAS and its product cGAMP are therapeutic targets. However, if cGAS functions independently of cGAMP signaling is undefined. Here, we identified an alternative signaling pathway that cGAS engages independent of cGAMP synthesis. We demonstrate that alternative cGAS signaling promotes hyperexpression of CXCL1 and enhanced neutrophil recruitment that facilitates viral dissemination during herpes simplex encephalitis. Our study reports of an alternative cGAS response independent of cGAMP, highlighting a previously uncharacterized scaffold function for cGAS.
    Keywords:  HSV; cGAS; infection; mouse model; type I IFN
    DOI:  https://doi.org/10.1073/pnas.2423873122
  21. J Allergy Clin Immunol. 2025 May 26. pii: S0091-6749(25)00575-5. [Epub ahead of print]
    Mast cells activated in vitro can modulate macrophage polarization and antibacterial responses.
    Dorothea B Holter, Sophie Zahalka, Jessica Brösamlen, Mariem Radhouani, Martin L Watzenboeck, Tyler J Artner, Asma Farhat, Riem Gawish, Karin Lakovits, Anastasiya Hladik, Federica Quattrone, Wolfgang Weninger, Thomas Krausgruber, Shane J F Cronin, Shweta Tikoo, Rohit Jain, Sylvia Knapp, Nikolaus Fortelny, Philipp Starkl.
       BACKGROUND: Mast cells and macrophages are tissue-resident immune cells frequently found in close proximity in barrier organs. Macrophages show high plasticity and microenvironmental factors, such as cytokines, can influence their phenotype. Mast cells are central in allergic reactions where allergens cause mast cell activation via antigen-specific IgE antibodies and the release of a multitude of inflammatory substances. While macrophages have clearly defined physiologic roles in tissue maintenance and host defense against microbes, biological mast cell functions are less well defined.
    OBJECTIVE: In the current study, we aimed to understand the interplay of mast cells and macrophages and how mast cell-released mediators can shape macrophage phenotype and function.
    METHODS: Using primary in vitro models of mast cells and macrophages combined with microscopic, functional, metabolic, genetic and epigenetic analyses, we investigate the macrophage polarization effects of mast cell mediators produced upon activation with IgE and antigen. We apply a macrophage engraftment strategy to explore potential in vivo implications of mast cell-mediated priming.
    RESULTS: We find that pre-formed and newly-synthesized mediators released by activated mast cells shape a macrophage phenotype different from the classical M1/M2 macrophage paradigm. Exposure to supernatant of activated mast cells induces epigenetic reprogramming of macrophages. This profound priming effect strongly alters macrophage phagocytosis, cytokine production and transcriptomic responses upon secondary exposure to bacteria or their products. Importantly, in vivo transfer of primed macrophages also significantly affects the outcome of sterile inflammation and bacterial peritonitis.
    CONCLUSION: Our study highlights the great potential of activated mast cells as directors of macrophage function.
    Keywords:  Allergy; IgE; LPS; activation; bacteria; degranulation; epigenetic; infection; macrophage; mast cell; polarization; priming
    DOI:  https://doi.org/10.1016/j.jaci.2025.02.040
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