bims-cediti Biomed News
on Cell death in innate immunity, inflammation, and tissue repair
Issue of 2026–02–01
twenty-one papers selected by
Kateryna Shkarina, Universität Bonn
  1. Spotted: RIPK3 and MLKL assembling necroptotic complexes.
  2. Dimerization-dependent gel-like condensation with dsDNA underpins the activation of human cGAS.
  3. Exosite-mediated targeting of GSDMB by dimeric granzyme A in lymphocyte pyroptotic killing.
  4. Lysosomes as hubs of metabolic sensing and cellular homeostasis.
  5. CARD9 orchestrates tissue damage in APAP-induced hepatitis via TREM2-mediated sensing cell death.
  6. Lipid scrambling via TMEM16F mediates the formation and release of extracellular vesicles.
  7. IRF2 deficiency disrupts pyroptosis, NK cell interferon-γ production and resistance to Francisella.
  8. p53 Interacts with VDAC1, Modulating Its Expression Level and Oligomeric State to Activate Apoptosis.
  9. Shigella flexneri evades septin-mediated cell-autonomous immunity via protein ADP-riboxanation.
  10. Cytosolic nucleic acid sensing triggers type I interferon activation via the Hippo kinase LATS1.
  11. Mitochondria as Inducers of Neutrophil Extracellular Traps.
  12. Non-Apoptotic Programmed Cell Death: From Ultrastructural Characterization to Emerging Therapeutic Opportunities.
  13. Factors that determine cell fate in mitotically arrested cancer cells.
  14. C-Type Lectin Receptors in Host Defense.
  15. Mitochondrial DNA: A Key Alarmin Igniting the Inflammasome Fire in Health and Disease.
  16. DNA-protein cross-links promote cGAS-STING-driven premature aging and embryonic lethality.
  17. Dose-dependent activation of the Hippo pathway by Type I and Type III interferons suppresses tissue repair by human bronchial epithelial cells.
  18. Mitochondria as sources and targets of cellular signaling.
  19. A Thermodynamic Constraint on GPx4 Flux Links Glutathione Redox State to Ferroptotic Commitment.
  20. Peritoneal neutrophil extracellular traps contribute to septic AKI via peritoneal IL-17A and distant organ CXCL-1/ CXCL-2 pathway in abdominal sepsis.
  21. Cysteine Reactivity Profiling Identifies Host Regulators of Mycobacterium tuberculosis Replication in Human Macrophages.
  1. Open Biol. 2026 Jan 28. pii: 250236. [Epub ahead of print]16(1):
    Spotted: RIPK3 and MLKL assembling necroptotic complexes.
    Verónica Martínez-Osorio, Uris Ros, Ana J García-Sáez.
      Necroptosis is a form of regulated cell death (RCD) that evolved as a defence against pathogenic infection. Unlike caspase-dependent RCD, necroptosis, in its canonical form, is driven by receptor-interacting protein kinase 1 and 3 (RIPK1 and RIPK3) signalling, culminating in the activation of the pseudokinase mixed lineage kinase domain-like protein (MLKL). Central to this process is the interaction between MLKL and its upstream regulator, RIPK3, forming a functional module called the necrosome that governs the spatiotemporal execution of cell death. Despite progress in our understanding of necroptotic signalling, key open questions remain. The structural organization of MLKL influences its interaction with RIPK3, yet the precise features of their binding surfaces and their regulation are not fully resolved. Additionally, the high-order supramolecular assembly of the necrosome and its transition between different states remain poorly understood, particularly regarding how RIPK3 and MLKL configurations impact necrosome activity and stability. In this review, we summarize current knowledge on the evolution, structure and regulation of the RIPK3-MLKL axis and discuss models of their activation in light of recent discoveries.
    Keywords:  MLKL; RIPK3; inflammation; membrane permeabilization; necroptosis
    DOI:  https://doi.org/10.1098/rsob.250236
  2. Cell Rep. 2026 Jan 23. pii: S2211-1247(25)01692-4. [Epub ahead of print]45(2): 116920
    Dimerization-dependent gel-like condensation with dsDNA underpins the activation of human cGAS.
    Jacob Lueck, Alexander Strom, Stephanie Martinez Torres, Shuai Wu, Jasper Moh, Hannah Wendorff, Brendan Antiochos, Jungsan Sohn.
      Cyclic G/AMP (cGAMP) synthase (cGAS) initiates inflammatory responses against pathogenic double-stranded (ds)DNA. Although it is well established that cGAS forms phase-separated condensates with dsDNA, its function remains poorly defined. We report here that the dimerization of cGAS on dsDNA creates a mesh-like network, leading to hydrogel-like condensate formation. While cGAS binds to and forms condensates with various nucleic acids, only dsDNA permits the dimerization necessary for activation and gelation. cGAS co-condenses dsDNA and other nucleic acids but retains a distinct dsDNA-mediated gel-like substate that can be dissolved by single-stranded RNA or short dsDNA. Moreover, compared with liquid-like condensates, we find that gel-like condensates are more effective not only in protecting bound dsDNA from exonucleases but also in limiting the mobility of nucleoside triphosphates and the dinucleotide intermediate for cGAMP synthesis. Together, our results show that enzymes can fine-tune surrounding microenvironments to regulate their signaling activities.
    Keywords:  CP: cell biology; CP: immunology; cGAS; condensates; gelation; innate immunity; phase separation; phase transition
    DOI:  https://doi.org/10.1016/j.celrep.2025.116920
  3. Immunity. 2026 Jan 26. pii: S1074-7613(25)00565-5. [Epub ahead of print]
    Exosite-mediated targeting of GSDMB by dimeric granzyme A in lymphocyte pyroptotic killing.
    Xiu Zhong, Ya Su, Zhiwei Zhou, Yuqiu Sun, Yanjie Hou, Feng Shao, Jingjin Ding.
      In cellular immunity, cytotoxic lymphocytes employ granzyme A (GZMA) to cleave and activate the pore-forming protein gasdermin B (GSDMB) for the pyroptotic killing of target cells. How GZMA recognizes and cleaves GSDMB is unknown. Here, we show that human GZMA targets GSDMB via specific, high-affinity binding to its autoinhibitory GSDMB-C domain. This binding requires the dimerization of GZMA, a unique property among human granzymes. A crystal structure of the GZMA-GSDMB-C complex shows a 2:2 stoichiometry, featuring an exosite at each of the two symmetric dimer interfaces in GZMA. The exosite engages a two-loop-organized site in the GSDMB-C domain, rendering a functional cleavage at Lys244 in GSDMB. Mouse GZMA (mGZMA) adopts a similar dimer structure, but its exosite is less efficient in engaging GSDMB. Mutation of the exosite enabled mGZMA to efficiently cleave and activate GSDMB. Our study reveals a substrate-targeting mechanism used by lymphocyte-derived granzymes to kill target cells.
    Keywords:  cell killing; cytotoxic lymphocytes; exosite; gasdermin B; granzyme A; pyroptosis
    DOI:  https://doi.org/10.1016/j.immuni.2025.12.009
  4. Mol Cell. 2026 Jan 28. pii: S1097-2765(26)00031-6. [Epub ahead of print]
    Lysosomes as hubs of metabolic sensing and cellular homeostasis.
    Aakriti Jain, Roberto Zoncu.
      Lysosomes are hubs that couple macromolecular breakdown to cell-wide signaling by sensing metabolic, damage-associated, and environmental cues. Nutrients liberated in the lysosomal lumen as end-products of macromolecular degradation, including amino acids, lipids, and iron, are exported by dedicated transporters for utilization in the cytoplasm. Nutrient transport across the lysosomal membrane is coupled to its sensing by specialized signaling complexes on the cytoplasmic face, which, in response, mediate communication with other organelles and control cell-wide programs for growth, catabolism, and stress response. Lysosomes acquire specialized sensing-signaling features in immune cells, where they shape antigen processing, innate immune signaling, and inflammatory cell death, and in neurons, where they act as sentinels of proteostatic and mitochondrial stress, supporting local translation, organelle quality control, and neuroimmune crosstalk. We highlight recently identified pathways and players that position lysosomes as integrators of nutrient status and organelle health to drive tissue-specific physiology.
    Keywords:  amyloid; autophagy; inflammation; lysosome; mTORC1; metabolites; neurodegeneration; organelle contacts; signaling
    DOI:  https://doi.org/10.1016/j.molcel.2026.01.011
  5. J Immunol. 2026 Jan 21. pii: vkaf222. [Epub ahead of print]215(1):
    CARD9 orchestrates tissue damage in APAP-induced hepatitis via TREM2-mediated sensing cell death.
    Zaopeng Yang, Shiqi Li, Renlin Lu, Zhanqi Wei, Xueqiang Zhao, Xin Lin.
      During the progression of acetaminophen (N-acetyl-para-aminophenol [APAP])-induced liver injury, the innate immune response is implicated in the induction of tissue damage. However, the precise cellular and molecular mechanisms underlying this process are not yet completely elucidated. CARD9 is known to modulate the activation of the NF-κB family of transcription factors during anti-pathogen immune responses, but its involvement in sterile APAP-induced hepatitis has not been heretofore studied. To investigate this, we employed an APAP-induced liver injury model, which simulates the initial toxic demise of hepatocytes, followed by innate immune activation. Our findings reveal that CARD9 expression within Kupffer cells exacerbates liver damage by amplifying the production of proinflammatory factors, which are known to play a pathological role in noninfectious conditions. Furthermore, our study identifies TREM2 receptors on Kupffer cells as capable of recognizing components released upon cell death and operating as upstream signaling receptors to orchestrate tissue damage during sterile inflammation.
    Keywords:  CARD9; Kupffer cells; TREM2; acetaminophen; tissue damage
    DOI:  https://doi.org/10.1093/jimmun/vkaf222
  6. Mol Biol Cell. 2026 Jan 28. mbcE25050245
    Lipid scrambling via TMEM16F mediates the formation and release of extracellular vesicles.
    Trieu Le, Maria Eugenia Perez Collado, Yu Meng Li, Amra Saric, Joost C M Holthuis, Sergio Grinstein, Spencer A Freeman.
      The ubiquitous and highly conserved programmed cell death pathways that are essential for tissue development and homeostasis are accompanied by distinct morphological alterations. Apoptotic cells undergo fragmentation that is concomitant with the exposure of phosphatidylserine (PS) on the membrane surface. Large fragments, called apoptotic bodies, as well as much smaller and more numerous vesicles are released. While the molecular mechanisms underlying apoptotic body formation have been explored, much less is known about vesicle biogenesis. We used an inducible, active form of TMEM16F to determine the role of lipid scrambling in vesiculation, separately from other apoptotic signaling events. Plasmalemmal lipid scrambling sufficed to release apoptotic-like vesicles without causing changes in cytosolic calcium or the submembrane cytoskeleton. The scrambled bilayer showed pronounced segregation of exofacial lipids and redistribution of detectable cholesterol to the inner leaflet. The clustering of raft-associated components with bulky headgroups-typified by glycophosphatidylinositol-linked proteins-formed domains of outward (convex) curvature, while regions of accumulation of phosphatidylethanolamine (PE) generated inward (concave) curvature that facilitated the scission of vesicles. Thus, scrambling of plasma membrane lipids suffices to induce regions of acute membrane curvature and facilitates detachment of vesicles analogous to those released from the surface of apoptotic cells.
    DOI:  https://doi.org/10.1091/mbc.E25-05-0245
  7. EMBO Rep. 2026 Jan 28.
    IRF2 deficiency disrupts pyroptosis, NK cell interferon-γ production and resistance to Francisella.
    Maxence Cornut, Sophia Djebali, Elena Rondeau, Sarah Dayet, Théo Fayolle, Julie Haagen, Lucie Fallone, Noémi Rousseaux, Emmanuelle Caspar, Mélissa Marcotte, Amandine Martin, Elise Courteboeuf, Maëlan Deschamps-Biboulet, Marie Teixeira, Jacqueline Marvel, Bénédicte F Py, Thierry Walzer, Antoine Marcais, Thomas Henry, Émilie Bourdonnay.
      IRF2 plays an indirect role in inflammasome activation by regulating Caspase-4 and Gasdermin D (GSDMD) levels. However, the in vivo relevance of this regulatory circuit is unknown. We generate IRF2KO mice and demonstrate that they are equally susceptible to Francisella novicida infection as GSDMDKO mice. Interestingly, the phenotypes of IRF2KO and GSDMDKO mice diverge with respect to IFN-γ. Specifically, IRF2KO mice exhibit a profound defect in IFN-γ production, which we attribute to an intrinsic role of IRF2 in regulating both the number and maturation of NK cells. IRF2KO NK cells fail to express the antibacterial effectors IL-18R and Granzyme A, thereby impairing bacterial clearance. IFN-γ therapy partially restores immune responses in IRF2KO mice and resistance to infection. These findings confirm IRF2 as a dual regulator of inflammasome activity and NK cell function, highlighting its pivotal role in innate immunity. Moreover, they underscore the potential of IFN-γ therapy as a promising treatment for severe infections in patients with primary immunodeficiencies affecting multiple immune pathways.
    Keywords:   Francisella novicida ; Gasdermin D; IFN- γ; IRF2; NK Cells
    DOI:  https://doi.org/10.1038/s44319-026-00698-4
  8. Biomolecules. 2026 Jan 13. pii: 141. [Epub ahead of print]16(1):
    p53 Interacts with VDAC1, Modulating Its Expression Level and Oligomeric State to Activate Apoptosis.
    Elinor Gigi, Aditya Karunanithi Nivedita, Danya Ben-Hail, Manikandan Santhanam, Anna Shteinfer-Kuzmine, Varda Shoshan-Barmatz.
      The p53 tumor suppressor, a key transcription factor, acts as a cellular stress sensor that regulates hundreds of genes involved in responses to DNA damage, oxidative stress, and ischemia. Through these actions, p53 can arrest cell cycle, initiate DNA repair, or trigger cell death. In addition to its nuclear functions, p53 can translocate to mitochondria to promote apoptosis. Studies using isolated mitochondria have suggested that p53 drives the voltage-dependent anion channel (VDAC1) into high molecular mass complexes to mediate apoptosis. VDAC1 is a central regulator of cellular energy production and metabolism and also an essential player in apoptosis, induced by various apoptotic stimuli and stress conditions. We previously demonstrated that VDAC1 oligomerization, induced by various apoptosis stimuli and stress conditions, forms a large pore that enables cytochrome c release from mitochondria, thereby promoting apoptotic cell death. In this study, we show that p53 interacts with VDAC1, modulates its expression levels, and promotes VDAC1 oligomerization-dependent apoptosis. Using purified proteins, we found that p53 directly binds VDAC1, as revealed by microscale thermophoresis and by experiments using bilayer-reconstituted VDAC1, in which p53 reduced VDAC1 channel conductance. Furthermore, overexpression of p53 in p53-null cells or in cells expressing wild-type p53 increased VDAC1 expression and induced VDAC1 oligomerization even in the absence of apoptotic stimuli. Together, these findings identify VDAC1 as a direct p53 target whose expression, oligomerization, and pro-apoptotic activity are regulated by p53. They also reinforce the central role of VDAC1 oligomerization in apoptosis.
    Keywords:  VDAC1; apoptosis; mitochondria; oligomerization; p53
    DOI:  https://doi.org/10.3390/biom16010141
  9. Nat Commun. 2026 Jan 27.
    Shigella flexneri evades septin-mediated cell-autonomous immunity via protein ADP-riboxanation.
    Zhiheng Tang, Wei Xian, Gizem Özbaykal Güler, Hanyu Zhang, Ying Wang, Naizheng Zhan, Huwei Liu, Fuping You, Qinghua Zou, Serge Mostowy, Xiaoyun Liu.
      Cell-autonomous immunity represents evolutionarily conserved defense mechanisms present in both immune and non-immune cells. One of such mechanisms is mediated by cytoskeletal septins that entrap cytosolic bacterial pathogens within cage-like structures. To promote infection, Shigella flexneri delivers effector proteins directly into host cells via a type III secretion system. Here we demonstrate that OspC effectors enable Shigella flexneri to evade septin cage entrapment. Mechanistically, OspC catalyzes ADP-riboxanation of SEPT9 at Arg561, a site essential for stabilizing septin hetero-oligomers. Notably, Arg561 ADP-riboxanation impairs septin polymerization and hence assembly of higher-order structures, including filaments and cage-like structures. Furthermore, we provide evidence that OspC effectors act synergistically with OspG to antagonize septin cage entrapment via two distinct post-translational modifications, thereby facilitating cell-to-cell spread and intracellular replication. Overall, our work reveals the elegant strategies of bacterial pathogens to evade septin-mediated cell-autonomous immunity and offers avenues for therapeutic intervention.
    DOI:  https://doi.org/10.1038/s41467-026-68425-0
  10. J Biol Chem. 2026 Jan 23. pii: S0021-9258(26)00074-8. [Epub ahead of print] 111204
    Cytosolic nucleic acid sensing triggers type I interferon activation via the Hippo kinase LATS1.
    Tim Nass, Anna D Reichardt, Saba R Aliyari, Emily Tom, Gage LeMunyan, Michelle S Parvatiyar, Genhong Cheng, Kislay Parvatiyar.
      Innate immune detection of viral genomes via nucleic acid sensing pattern recognition receptors in the cytosolic compartment triggers the production of type I interferons (IFN-I) to coordinate a cellular antiviral state to limit viral replication and spread. While IFN-I induction is controlled primarily by the IRF3 transcription factor which undergoes phosphorylation dependent activation via the virus activated kinase, TBK1, the mechanisms underlying how TBK1 signaling is achieved remains incompletely understood. Here we report that viral infection or cytosolic delivery of nucleic acids elicits the activation of a primordial Hippo signaling pathway that is known to control organ size and tissue homeostasis. We identify the Hippo core component, LATS1 kinase to necessitate TBK1 dependent signaling as cells treated with a pharmacological inhibitor of LATS1 or cells from Lats1-/- mice displayed impaired TBK1-IRF3 signal activities and defective IFN-I induction upon cytosolic nucleic acid stimulation. Consequently, LATS1 deficient cells harbored elevated viral titers in comparison to WT control cells. Mechanistically, LATS1 associated with TBK1 upon cytosolic nucleic acid stimulation and promoted TBK1 signaling and activation in a kinase dependent manner. Altogether, our findings reveal that cytosolic nucleic acid sensing pathways elicit Hippo/LATS1 activation to govern TBK1 signaling events to result in IFN-I activation.
    Keywords:  Hippo signaling; Large tumor suppressor 1 (LATS1); TANK binding kinase 1 (TBK1); innate antiviral signaling; interferon regulatory factor 3 (IRF3); pattern recognition receptors (PRRs); type I interferon (IFN-I)
    DOI:  https://doi.org/10.1016/j.jbc.2026.111204
  11. Inflammation. 2026 Jan 26.
    Mitochondria as Inducers of Neutrophil Extracellular Traps.
    Emil Bečka, Letícia Hudecová, Michal Pastorek.
      Neutrophil extracellular traps (NETs) represent a critical immune defense mechanism that can become pathological in sterile inflammation. Mitochondrial damage-associated molecular patterns (mtDAMPs) emerge as particularly potent triggers of NET formation due to their bacterial-like molecular features inherited from endosymbiotic origins. This review examines the mechanisms by which key mtDAMPs, including mitochondrial DNA, ATP, cardiolipin, cytochrome c, succinate, heme and formylated peptides, induce NETosis through pattern recognition receptors typically reserved for pathogen detection. We describe the complex signaling networks downstream of mtDAMP recognition, highlighting the roles of membrane and intracellular receptors and mitogen-activated protein kinase pathways in orchestrating mtDAMP-induced NET formation. The clinical relevance of mtDAMP-induced NETosis is explored across trauma and wound healing contexts, where neutrophil phenotype along with concentration-dependent and temporal dynamics determine beneficial versus pathological outcomes. Current therapeutic approaches modulating NET formation are discussed challenges in stimulus specificity, pathway redundancy, and use of analgesics and anti-inflammatory drugs. We conclude with future research priorities that include establishing clinically relevant concentration thresholds, elucidating synergistic mtDAMP effects, and developing targeted therapeutic strategies for NET-mediated pathology in sterile inflammatory conditions.
    Keywords:  DAMP; Mitochondria; Neutrophil; Neutrophil extracellular traps
    DOI:  https://doi.org/10.1007/s10753-025-02432-z
  12. Cells. 2026 Jan 08. pii: 111. [Epub ahead of print]15(2):
    Non-Apoptotic Programmed Cell Death: From Ultrastructural Characterization to Emerging Therapeutic Opportunities.
    Philip Steiner, Lena Wiesbauer, Hubert H Kerschbaum, Susanna Zierler.
      Distinct forms of non-apoptotic programmed cell death (PCD) play a central role in human and animal health and their signaling cascades provide pharmacological targets for therapeutic interventions. Non-apoptotic modalities of programmed cell death include well characterized forms, such as ferroptosis, necroptosis, pyroptosis, autophagy, paraptosis, as well as newly characterized varieties, such as cuproptosis, disulfidptosis, and erebosis. Each pathway exhibits unique molecular signaling signatures, ultrastructural characteristics, and functional outcomes that distinguish them from classical apoptosis. While pharmacological targets in the signaling cascade are promising objectives for overcoming apoptosis resistance in cancer therapy, inhibition of cell death in the myocardium or nervous system is critical for cytoprotection. This review provides detailed characterization and schematic visualization of cellular and subcellular hallmarks for each non-apoptotic PCD modality, facilitating their morphological identification. Understanding these diverse pathways is crucial for developing innovative therapeutic interventions in cancer, neurodegeneration, and inflammatory diseases.
    Keywords:  autophagy; autosis; cancer; caspase-independent cell death; ferroptosis; neurodegenerative diseases; non-apoptotic cell death; programmed cell death; regulated cell death; ultrastructure
    DOI:  https://doi.org/10.3390/cells15020111
  13. Front Cell Dev Biol. 2025 ;13 1691574
    Factors that determine cell fate in mitotically arrested cancer cells.
    Naghmana Ashraf, Roaa Kassim, Edward Goldstein, Taylor Landfair, Clarissa G Nuñez, Jeffrey B Arterburn, Charles B Shuster.
       Introduction: Cancer cells display a high degree of heterogeneity in their responses to mitotic arrest, from apoptosis during mitosis to surviving mitotic failure and continuing to progress through the cell cycle. Thus, understanding the basis for this variation may prove valuable for developing more effective chemotherapeutic strategies.
    Methods: A combination of biochemical and long-term live cell imaging approaches were applied to determine whether inhibition of Phosphoinositide 3-kinase (PI3K) signaling affected apoptosis in cancer cells arrested in prometaphase with a Kinesin Spindle Protein (KSP) inhibitor.
    Results: Dual inhibition of KSP and PI3K signaling induced apoptosis more effectively than mitotic arrest or PI3K pathway inhibition alone. Live cell imaging with probes for mitotic progression and apoptosis revealed that HeLa cells that died during mitotic slippage underwent apoptosis during prometaphase arrest, suggesting that PI3K inhibition dramatically shifted the dynamics of cell death. Similar potentiation of mitotic cell death could be detected in SiHa cells, whereas other cancer or non-transformed cell lines were not sensitized by PI3K inhibition. Expression of constitutively active Rap1, which modulates both cell adhesion and PI3K activity, significantly increased the duration of mitotic arrest in a PI3K-dependent manner. Moreover, activated Rap1 significantly increased the fraction of cells that slipped completely back into interphase prior to apoptotic cell death.
    Conclusions: These results shed insights into possible mechanisms by which cells may evade cell death during mitotic delay and suggest a strategy to optimize antimitotic interventions.
    Keywords:  Rap1; apoptosis; kinesin spindle protein; mitosis; mitotic slippage; phosphoinositide-3-kinase
    DOI:  https://doi.org/10.3389/fcell.2025.1691574
  14. Annu Rev Immunol. 2026 Jan 27.
    C-Type Lectin Receptors in Host Defense.
    Sonja I Gringhuis, Teunis B H Geijtenbeek.
      C-type lectin receptors (CLRs) present on myeloid cells provide crucial signals for the induction of innate and adaptive immune responses. Their broad ligand specificity places them in a perfect position to sense both microbial intruders and signs of tissue injury or cell death. In this article, we review the mechanisms that link CLR engagement to tailored cellular responses against those perceived threats. We discuss not only how molecular interplay between signaling by CLRs and by other pattern recognition receptors fine-tunes host-protective responses but also how these receptors can lead to pathological immune responses. An understanding of how these responses are regulated may offer strategies for treating not just infectious diseases but also autoimmune or malignant disorders.
    DOI:  https://doi.org/10.1146/annurev-immunol-083024-035049
  15. Immunology. 2026 Jan 29.
    Mitochondrial DNA: A Key Alarmin Igniting the Inflammasome Fire in Health and Disease.
    Woo Hyun Park.
      Beyond their classical role as cellular powerhouses, mitochondria are now recognised as indispensable hubs for innate immune signalling. A pivotal aspect of this function is the release of mitochondrial DNA (mtDNA), a potent damage-associated molecular pattern (DAMP) that, when misplaced, acts as a powerful alarmin due to its prokaryotic origins. In response to cellular stress or infection, mtDNA translocates to the cytosol and activates intracellular protein platforms known as inflammasomes, triggering the maturation of cytokines like interleukin-1β (IL-1β) and inducing a lytic form of cell death, pyroptosis. This review synthesises current research on this intricate relationship. Whilst potassium (K+) efflux remains the canonical trigger for the NLR family pyrin domain containing 3 (NLRP3) inflammasome, emerging and debated roles of oxidised mtDNA (ox-mtDNA) as a potential direct ligand or critical upstream amplifier are explored. The manuscript elucidates mtDNA release mechanisms, such as mitochondrial permeability transition pore (mPTP) opening, and explores the role of amplifying pathways like the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) axis and cytidine/uridine monophosphate kinase 2 (CMPK2)-mediated mtDNA synthesis. The profound involvement of the mtDNA-inflammasome axis is surveyed across a spectrum of pathologies, including autoimmune, metabolic, neurodegenerative, and cardiovascular diseases. The compiled evidence establishes mtDNA as a universal trigger of inflammation and a unifying pathogenic driver across this diverse disease landscape, highlighting the significant therapeutic potential of modulating this fundamental immune signalling axis to treat a multitude of human diseases.
    Keywords:  immunogenic cell death; inflammasome; innate immunity; mitochondrial DNA; pyroptosis; sterile inflammation
    DOI:  https://doi.org/10.1111/imm.70111
  16. Science. 2026 Jan 29. 391(6784): eadx9445
    DNA-protein cross-links promote cGAS-STING-driven premature aging and embryonic lethality.
    Ines Tomaskovic, Cristian Prieto-Garcia, Maria Boskovic, Mateo Glumac, Tsung-Lin Tsai, Thorsten Mosler, Rubina Kazi, Rajeshwari Rathore, Jorge Andrade, Marina Hoffmann, Giulio Giuliani, Anne-Claire Jacomin, Raquel S Pereira, Elias Knop, Laurens Wachsmuth, Petra Beli, Koraljka Husnjak, Manolis Pasparakis, Andrea Ablasser, Daniela S Krause, Michael Potente, Stamatis Papathanasiou, Janos Terzic, Ivan Dikic.
      DNA-protein cross-links (DPCs) are highly toxic DNA lesions that block replication and transcription, but their impact on organismal physiology is unclear. We identified a role for the metalloprotease SPRTN in preventing DPC-driven immunity and its pathological consequences. Loss of SPRTN activity during replication and mitosis lead to unresolved DNA damage, chromosome segregation errors, micronuclei formation, and cytosolic DNA release that activates the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. In a Sprtn knock-in mouse model of Ruijs-Aalfs progeria syndrome, chronic cGas-Sting signaling caused embryonic lethality through inflammation and innate immune responses. Surviving mice displayed aging phenotypes beginning in embryogenesis, which persisted into adulthood. Genetic or pharmacological inhibition of cGas-Sting rescued embryonic lethality and alleviated progeroid phenotypes.
    DOI:  https://doi.org/10.1126/science.adx9445
  17. PLoS Biol. 2026 Jan 26. 24(1): e3003615
    Dose-dependent activation of the Hippo pathway by Type I and Type III interferons suppresses tissue repair by human bronchial epithelial cells.
    Krupakar V Subramaniam, Hui Jing Lim, Bao Wang, Valia T Mihaylova, Evrett N Thompson, Diane S Krause, Ellen F Foxman.
      Interferons (IFNs) are potent antiviral cytokines that are rapidly activated when infected cells sense a virus, but continued IFN production following acute infection is linked to impaired recovery. IFNs protect against infection by inducing a suite of antiviral effectors in IFN receptor-expressing cells via JAK/STAT signaling. However, how IFNs curtail tissue repair is not fully understood. Here, we studied the effects of Type III IFNs (IFNλ1 and IFNλ2) and Type I IFN (IFNβ) on tissue repair functions of human bronchial epithelial cells (HBEC). We show that both Type III IFNs and IFNβ reduce bronchial epithelial cell migration and proliferation through a common upstream mechanism: activation of LATS1, a kinase best known for limiting organ growth as part of the Hippo signaling pathway. Mechanistically, Type III IFN or IFNβ curtailed wound healing by triggering phosphorylation of LATS1 via JAK activity, bypassing activation of MST1/2, the canonical activator of LATS1 in the Hippo pathway. Further experiments showed that distinct signaling pathways lead to LATS1 and STAT1 phosphorylation downstream of IFN receptor signaling. STAT1 was dispensable for IFN-mediated LATS1 phosphorylation and suppression of tissue repair, although as expected STAT1 was required for IFN-mediated protection from rhinovirus or influenza infection. Dose-response curve experiments revealed that higher concentrations of IFN were required to trigger LATS1 phosphorylation compared to STAT1 phosphorylation. Consistently, during rhinovirus or influenza virus infection of organotypic HBEC cultures, we observed phosphorylation of both LATS1 and STAT1, but with different kinetics, with LATS1 activation showing earlier resolution compared to STAT1 activation. These results provide a conceptual framework for understanding how IFN receptor signaling differentially controls epithelial functions required for tissue repair and antiviral defense, and inform efforts to target pathological effects of IFNs following viral infection and in other high IFN states.
    DOI:  https://doi.org/10.1371/journal.pbio.3003615
  18. Mol Cell. 2026 Jan 28. pii: S1097-2765(26)00028-6. [Epub ahead of print]
    Mitochondria as sources and targets of cellular signaling.
    Anna Meichsner, Verian Bader, Konstanze F Winklhofer.
      Mitochondria are multifunctional organelles that, in addition to providing energy, coordinate various signaling pathways essential for maintaining cellular homeostasis. Their suitability as signaling organelles arises from a unique combination of structural and functional plasticity, allowing them to sense, integrate, and respond to a wide variety of cellular cues. Mitochondria are highly dynamic-they can fuse and divide, pinch off vesicles, and move around, facilitating interorganellar communication. Moreover, their ultrastructural peculiarities enable tight regulation of fluxes across the inner and outer mitochondrial membranes. As organelles of proteobacterial origin, mitochondria harbor danger signals and require protection from the consequences of membrane damage by efficient quality control mechanisms. However, mitochondria have also been co-opted by eukaryotic cells to react to cellular damage and promote effective immune responses. In this review, we provide an overview of our current knowledge of mitochondria as both sources and targets of cellular signaling.
    Keywords:  ISR; MAVS; NEMO; NF-κB; UPRmt; cGAS/STING; cardiolipin; inflammation; innate immune signaling; membrane contact sites; mitochondria; mtDNA; mtRNA; signaling
    DOI:  https://doi.org/10.1016/j.molcel.2026.01.008
  19. Free Radic Biol Med. 2026 Jan 23. pii: S0891-5849(26)00057-2. [Epub ahead of print]
    A Thermodynamic Constraint on GPx4 Flux Links Glutathione Redox State to Ferroptotic Commitment.
    Fulvio Ursini, Antonella Roveri, Matilde Maiorino, Laura Orian.
      Ferroptosis is a non-accidental form of cell death driven by lipid peroxidation and critically controlled by the selenoenzyme Glutathione Peroxidase 4 (GPx4). By integrating molecular modeling, redox thermodynamics, and enzymatic evidence, we propose that ferroptosis is governed by the redox potential of the glutathione couple, elevating current mechanistic descriptions to a quantitative physical-chemical framework. The terminal step of the GPx4 catalytic cycle-responsible for enzyme regeneration and oxidized glutathione (GSSG) formation-is intrinsically endergonic, and its driving force declines continuously as the glutathione redox potential becomes less reducing. As a result, GPx4 activity decreases linearly in accordance with Nernstian principle, independently of discrete inhibitory events. Within this framework, ferroptosis is not initiated by a discrete molecular trigger or canonical signaling cascade; rather, it emerges when a critical biological threshold is surpassed, such that GPx4-dependent detoxification capacity is no longer sufficient to counteract ongoing lipid peroxidation within a given pro-oxidant context. Thus, a discrete cell-death outcome executed by GSSG emerges from the continuous variation of a thermodynamic control variable. This mode of regulation is unique to selenium chemistry and provides a physical-chemical rationale for the indispensability of selenocysteine in the redox control of cellular life and death.
    Keywords:  Ferroptosis; GPx4; Glutathione peroxidases; Glutathione redox potential; Lipid peroxidation; Redox homeostasis; Redox thermodynamics; Selenocysteine
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.01.039
  20. Sci Rep. 2026 Jan 27.
    Peritoneal neutrophil extracellular traps contribute to septic AKI via peritoneal IL-17A and distant organ CXCL-1/ CXCL-2 pathway in abdominal sepsis.
    Yoshitaka Naito, Daiki Goto, Naoki Hayase, Xuzhen Hu, Peter S T Yuen, Robert A Star.
      There are no specific treatments for Sepsis-associated acute kidney injury (AKI). We previously reported that Il-17a-knockout mice had dramatically improved survival after cecal ligation and puncture (CLP). Neutrophil extracellular traps (NETs) induce IL-17A, which causes harm in some diseases, but this pathway is poorly understood in sepsis. We found that knockout of Pad4 (Peptidyl Arginine Deiminase 4), an enzyme essential for NET formation, improved survival and AKI, and suppressed neutrophil infiltration into remote organs, involving a peritoneal IL-17A/distant organ CXCL-1/CXCL-2 pathway after CLP. NETs were detected in the peritoneal cavity, and not in plasma or distant organs. Adoptive transfer of peritoneal WT neutrophils restored the IL-17A/CXCL-1/CXCL-2 pathway in Pad4KO mice, leading to neutrophil infiltration and damage to remote organs. These results revealed a pathway from peritoneal NET formation to remote organ injury/inflammation via production of IL-17A at the infectious site and distant organ CXCL-1/CXCL-2. While NETs promoted intraperitoneal IL-17A production, we also showed that conversely, peritoneal IL-17A or CXCL-1/CXCL-2 promoted intraperitoneal NET formation after CLP. This peritoneal vicious cycle that includes NET formation, IL-17A, CXCL-1/CXCL-2 that may amplify sepsis-associated organ injury. Breaking this vicious cycle by inhibiting NET formation and/or IL-17A might be a promising therapeutic target for sepsis treatment.
    DOI:  https://doi.org/10.1038/s41598-025-34770-1
  21. ACS Infect Dis. 2026 Jan 27.
    Cysteine Reactivity Profiling Identifies Host Regulators of Mycobacterium tuberculosis Replication in Human Macrophages.
    John K Neff, Kristen E DeMeester, Paola K Párraga Solórzano, Radu M Suciu, Melissa M Dix, Gabriel Simon, Max A Gianakopoulos, Bruno Melillo, Benjamin F Cravatt, Michael U Shiloh.
      Innate immune cells, such as monocytes and macrophages, provide the earliest defense against intracellular pathogen infection by initiating signaling pathways and restricting pathogen replication. However, the full complement of proteins that mediate cell-autonomous immunity remains incompletely defined. Here, we applied cysteine-directed activity-based protein profiling (ABPP) to map proteome-wide cysteine reactivity changes in THP-1 monocytes and primary human monocyte-derived macrophages during Mycobacterium tuberculosis (Mtb) infection. Across both cell types, we quantified 148 cysteine residues with altered reactivity. Knockdown of a subset of proteins harboring infection-induced reactivity significantly altered Mtb replication in THP-1 monocytes, linking proteins with reactive cysteines to antimicrobial defense. These data define previously unrecognized host protein changes during Mtb infection and provide a resource for investigating post-translational events that regulate innate immune responses to intracellular bacteria.
    Keywords:  Mycobacterium tuberculosis; chemical proteomics; covalent probes; cysteine; innate immunity; macrophage; mass spectrometry
    DOI:  https://doi.org/10.1021/acsinfecdis.5c00984
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