bims-cediti Biomed News
on Cell death in innate immunity, inflammation, and tissue repair
Issue of 2026–09–20
seventeen papers selected by
Kateryna Shkarina, Universität Bonn
  1. NAD+ depletion by catalytic TIR domains triggers a distinct form of regulated necrosis in mammalian cells.
  2. Reverse genetics in humanized mice reveals CARD8-mediated pyroptosis causing pancytopenia in human DPP9 deficiency.
  3. ZBP1 evolution and antagonism by large DNA viruses.
  4. Antioxidant defenses of Francisella tularensis perturb Aim2 inflammasome activation.
  5. Chromatin decompaction within the nucleus increases plasma membrane tension promoting NETosis execution, independently of transcription.
  6. Decreased FSP1 expression under chronic hypoxia sensitizes human macrophages towards ferroptosis.
  7. Defensive lipid droplets are PUFA reservoirs and suppliers driving bacterial clearance and inflammation.
  8. Polymicrobial-driven NLRP6 inflammasome regulates IL-1β production and alveolar bone loss in a murine model of periodontitis.
  9. Alox15 restrains glycolysis to support M2 macrophage effector function during helminth immunity.
  10. Regulation of immune signal integration and memory by inflammation-induced chromosome conformation.
  11. Cysteine excess triggers a mitochondrial iron-dependent cell death.
  12. A high-density CRISPR activation platform for mapping cancer dependencies and resistance pathways ex vivo and in vivo.
  13. Programmed ribosomal frameshifting triggers translational stress to promote viral replication.
  14. Lactylation and regulated cell death: the substrate defines the outcome.
  15. Evolutionary conservation analysis reveals a primordial function of STING as a regulator of lipid metabolism via FADS2.
  16. Mitochondrial fission factor senses and governs ferroptosis.
  17. DFCP1-containing ER microdomains mediate lysosomal membrane repair.
  1. Proc Natl Acad Sci U S A. 2026 Sep 22. 123(38): e2604325123
    NAD+ depletion by catalytic TIR domains triggers a distinct form of regulated necrosis in mammalian cells.
    Nino A Espinas, Louise Lacante, Ella Hartenian, Vanessa Mack, Zhen-Xian Niou, Hui-Chen Lu, Petr Broz.
      Proteins containing Toll/interleukin-1 receptor (TIR) domains with catalytic NADase activity have recently emerged as major regulators of innate immunity in both bacteria and plants. In humans, however, only a single protein-SARM1-exhibits TIR-dependent NADase activity. Initially reported to act as a negative regulator of Toll-like receptor (TLR) signaling, SARM1-mediated NAD+ hydrolysis is now recognized as the central driver of Wallerian degeneration, a regulated form of axonal cell death that occurs following injury. Here, we demonstrate that suppression of TLR signaling by SARM1 requires its NADase activity and correlates with the induction of host cell death. Furthermore, we show that immune suppression by the Staphylococcus aureus effector TirS similarly relies on its ability to hydrolyze NAD+ and induce host cell death. Further analysis of TIR-induced cell death shows that it constitutes a form of regulated necrosis that is independent of known programmed cell death pathways. Comparative analysis of a panel of animal, bacterial, and plant TIR domains reveals that, in mammalian cells, TIR-induced cell death primarily results from the depletion of cellular NAD+ levels, and not from the accumulation of specific NAD+ hydrolysis products. Together, these findings implicate NAD+ depletion and the induction of host cell death as the main mechanism by which catalytic TIR domains suppress innate immunity.
    Keywords:  NAD+ hydrolysis; SARM1; TIR domain; TLR signaling; cell death
    DOI:  https://doi.org/10.1073/pnas.2604325123
  2. J Clin Invest. 2026 Sep 15. pii: e207530. [Epub ahead of print]136(18):
    Reverse genetics in humanized mice reveals CARD8-mediated pyroptosis causing pancytopenia in human DPP9 deficiency.
    Tianli Xiao, J Richard Brewer, Maximillian Carlino, Ailin Han, Yamato J Takabe, Chia-Yi Lee, Fengrui Zhang, Mi Chen, Holly Nicole Blackburn, Amin H Nassar, Qiankun Wang, Kristen Brennand, Liang Shan, Esen Sefik, Diane S Krause, Richard A Flavell.
      Loss-of-function mutation in the human gene dipeptidyl peptidase 9 (DPP9) causes Hatipoglu syndrome leading to severe inflammasomopathy. A key feature of the disease is pancytopenia, and patients require bone marrow transplantation, but the mechanism of cell loss is unclear, since Dpp9-mutant mice have normal hematopoiesis, suggesting that a distinct mechanism of disease occurs in humans. Here, we present a model of human DPP9 deficiency leveraging reverse genetics in the MISTRG6 humanized mice. We found that CRISPR editing of human CD34+ hematopoietic stem and progenitor cells (HSPCs) led to very efficient and persistent gene deletion in vivo. Human DPP9 deletion recapitulated cytopenia in peripheral blood and in the bone marrow, and cell loss was cell intrinsic. However, DPP9 deletion led to few transcriptional changes suggesting posttranscriptional regulation in human HSPCs. Mechanistically, DPP9 deficiency led to activation of the CARD8 inflammasome, resulting in HSPC pyroptosis, whereas NLRP1 was dispensable for cell death. Thus, our results reveal a unique human mechanism of disease and offer therapeutic insight for this inflammasomopathy.
    Keywords:  Hematology; Hematopoietic stem cells; Immunology; Innate immunity
    DOI:  https://doi.org/10.1172/JCI207530
  3. J Mol Biol. 2026 Sep 17. pii: S0022-2836(26)00399-2. [Epub ahead of print] 170026
    ZBP1 evolution and antagonism by large DNA viruses.
    Mamadou Amadou Diallo, Jonathan Maelfait.
      ZBP1 is a nucleic acid receptor that restricts virus infection by activating an inflammatory gene response and by inducing host cell death. Left-handed Z-form nucleic acids accumulating in infected cells activate ZBP1 by binding to its N-terminal Zα domains. Signal transduction relies on the presence of RIP homotypic interaction motifs (RHIMs) that recruit the RIPK1 and RIPK3 signalling kinases to induce NF-κB activation or cell death under the forms of apoptosis or necroptosis. The expression of Zα domain proteins by poxviruses and RHIM-containing proteins by herpesviruses that antagonise ZBP1 may reflect a long-standing evolutionary interaction between ZBP1-mediated immunity and large DNA viruses. Phylogenetic analysis shows that ZBP1 likely emerged during jawed vertebrate speciation with ZBP1 orthologues first appearing in cartilaginous fish. ZBP1 is subsequently lost in entire vertebrate clades, including bony fish, scaled reptiles, birds, marsupials, and rabbits and hares, suggesting reoccurring counterselection of ZBP1-based immunity. Evidence of a ZBP1-like protein in distantly related bivalve molluscs indicates that sensing of Z-form nucleic acids coupled to RHIM-mediated signal transduction has evolved at least twice throughout the animal kingdom. Here, we study the origins, structure and function of ZBP1 and its Zα domains and RHIMs, discuss their respective roles in sensing Z-nucleic acids and signal transduction, and review ZBP1's mutually antagonistic relationship with large DNA viruses.
    Keywords:  RIPK1; RIPK3; Z-DNA; Z-RNA; necroptosis
    DOI:  https://doi.org/10.1016/j.jmb.2026.170026
  4. Infect Immun. 2026 Sep 15. e0045326
    Antioxidant defenses of Francisella tularensis perturb Aim2 inflammasome activation.
    Zhuo Ma, Jacob Miller, Kayla Fantone, Chandra Shekhar Bakshi, Meenakshi Malik.
      Francisella tularensis is a gram-negative bacterium that causes tularemia, a fatal zoonotic disease. F. tularensis has been used in the bioweapon programs of several countries. Its potential use as a bioterrorism agent led the CDC to classify F. tularensis as a Tier 1 Select Agent. The cytosolic sensor absent in melanoma 2 (Aim2) detects double-stranded DNA in the cytosol of infected cells and subsequently assembles a multiprotein complex known as the inflammasome. Inflammasome activation drives the secretion of IL-1β and IL-18, key pro-inflammatory cytokines required for controlling F. tularensis infection. Prior studies have shown that F. tularensis actively suppresses Aim2 inflammasome activation; however, the underlying mechanism remains unknown. We hypothesized that F. tularensis suppresses Aim2-mediated responses by modulating the intracellular redox environment. We utilized an F. tularensis live vaccine strain (LVS) mutant lacking OxyR (ΔoxyR), a transcriptional regulator that controls the expression of major antioxidant enzymes. Our results show that macrophages infected with the ΔoxyR mutant exhibit significantly higher levels of Aim2-dependent caspase-1 and IL-1β than those infected with wild-type bacteria. The expression of interferon regulatory factor 1 and the guanylate-binding proteins GBP2 and GBP5, upstream signaling components of the Aim2 inflammasome, is markedly higher in ΔoxyR-infected macrophages than in controls. These changes were absent in ΔoxyR-infected NADPH oxidase-deficient macrophages, which are unable to generate reactive oxygen species. Collectively, these findings demonstrate that the macrophage redox environment plays a key role in activating the Aim2 inflammasome. This work advances understanding of how F. tularensis-encoded factors subvert host innate immune defenses.
    Keywords:  Francisella tularensis; absent in melanoma; antioxidant defenses; immunosuppression; inflammasome
    DOI:  https://doi.org/10.1128/iai.00453-26
  5. Nat Commun. 2026 Aug 20. pii: 9938. [Epub ahead of print]17(1):
    Chromatin decompaction within the nucleus increases plasma membrane tension promoting NETosis execution, independently of transcription.
    Aidan T Cabral, Manasi Sawant, Minwoo Kang, Liangqi Xie, Hawa Racine Thiam.
      Chromatin organizes DNA and regulates nuclear mechanics. However, whether and how chromatin regulates whole-cell mechanics and functions independently of transcription is largely unknown. Here, leveraging transcription-independent NETosis, we show that chromatin decompaction within the nucleus increases plasma membrane tension and cell volume. Mechanistically, we show that chromatin accessibility gradually increases and chromatin binding proteins (CBPs) H1, HP1α, and H3 differentially dissociate from chromatin as it decompacts during NETosis. We posit that dissociated CBPs become osmolytes that alter cellular osmolarity. Consistently, tuning extracellular osmolarity or disrupting regulators of membrane tension and cell volume (mTORC1/2, NHEs, or VRAC ion channels) alters plasma membrane rupture and NETosis execution. In non-NETing U2OS cells, decompacting chromatin increases membrane tension, independently of the cytoskeleton, indicating a causal relationship between chromatin organization and membrane tension. This work shows chromatin as a regulator of whole-cell mechanics, broadening our understanding of the non-genetic roles of chromatin in cell pathophysiology.
    DOI:  https://doi.org/10.1038/s41467-026-76578-1
  6. Redox Biol. 2026 Sep 17. pii: S2213-2317(26)00405-2. [Epub ahead of print]97 104406
    Decreased FSP1 expression under chronic hypoxia sensitizes human macrophages towards ferroptosis.
    Anja Wickert, Anna Schwantes, Yara Shadid, Sofie P Meyer, Bernhard Brüne, Dominik C Fuhrmann.
      Ferroptosis, an iron-dependent cell death, emerged as a new therapeutic approach to treat diseases such as cancer or diabetes. Several pathological conditions are characterized by the appearance of chronic hypoxia, which is known to attract immune cells, especially monocytes and macrophages. Therefore, we investigated how chronic hypoxia affects ferroptosis in primary human macrophages and THP-1 cells. Chronic but not acute hypoxia sensitized cells towards ferroptosis, in line with elevated cellular as well as mitochondrial lipid peroxides, and mitochondrial ROS. Time kinetics revealed an earlier increase in lipid peroxidation under chronic hypoxia compared to normoxia, which was followed by mitochondrial lipid peroxidation and mitochondrial ROS. Mechanistically, and in contrast to normoxia and/or acute hypoxia, chronic hypoxia diminished nuclear abundance and activity of the antioxidant transcription factor NRF2. Consequently, NRF2 target gene expression, including ferroptosis suppressor protein 1 (FSP1), decreased. Inhibition or knockdown of FSP1 mimicked the ferroptosis-sensitizing effect of chronic hypoxia. To causatively link decreased NRF2 activity to increased ferroptosis under hypoxia, we inhibited KEAP1, which preserved NRF2 activity, increased FSP1 expression, and decreased ferroptosis. Our data provides novel insights into NRF2 regulation under chronic hypoxia linked to FSP1 expression and ferroptosis sensitivity of primary human macrophages.
    Keywords:  AIFM2; Lipid peroxidation; NRF2; THP-1
    DOI:  https://doi.org/10.1016/j.redox.2026.104406
  7. Cell Rep. 2026 Sep 16. pii: S2211-1247(26)01080-6. [Epub ahead of print]45(10): 118002
    Defensive lipid droplets are PUFA reservoirs and suppliers driving bacterial clearance and inflammation.
    Marta Bosch, Gyana-Lipsa Parida, Marina Sánchez-Quijada, Carles Ruiz-Mirapeix, Miguel Sánchez-Álvarez, Laura Pedró-Cos, Alba Fajardo, Harriet P Lo, Mariano Alonso-Bivou, Rémi Safi, Erika Pineda, James Rae, James E B Curson, Bernhard Keller, Jesús Balsinde, Anna M Planas, Matthew J Sweet, Albert Herms, Caroline Demangel, Robert G Parton, Albert Pol.
      Lipid droplets (LDs) rapidly form in infected cells to participate in the defense against microbes. Here, we investigate the involvement of LD lipids in the immune response. Comparative lipidomics demonstrate that in vivo host LDs accumulate polyunsaturated fatty acids (PUFAs) in LD-triglycerides and -phospholipids. Host lipid metabolism and the LD proteome are transcriptionally controlled by rapid, transient, and intricate immune programs initiated by pathogen-associated molecular patterns and relayed by cytokines such as interferons (type I and II), interleukins (IL-1β), and tumor necrosis factor. When this environment is reproduced in cultured macrophages, newly formed LDs accumulate defensive proteins, coordinate complex PUFA synthesis, and become PUFA reservoirs and suppliers. Among LD-PUFAs, the ω-6 arachidonic acid is the most actively metabolized during the initial phases of innate immunity. Released from LDs by adipose triglyceride lipase, arachidonic acid is used by macrophages for prostaglandin and thromboxane synthesis, bacterial phagocytosis, and elimination of microbes.
    Keywords:  CP: metabolism; CP: microbiology; adipose triglyceride lipase; arachidonic acid; inflammation; innate immunity; lipid droplets; polyunsaturated fatty acids
    DOI:  https://doi.org/10.1016/j.celrep.2026.118002
  8. PLoS Pathog. 2026 Sep;22(9): e1014574
    Polymicrobial-driven NLRP6 inflammasome regulates IL-1β production and alveolar bone loss in a murine model of periodontitis.
    Sarah Metcalfe, Rajendra P Settem, Edwin J Ovalle, Michelle Panasiewicz, Alejandro Escobar, Jason G Kay.
      Periodontal disease is a chronic inflammatory condition that develops in response to oral microbiome dysbiosis and host-microbiome immune response dysregulation. The innate immune system plays a major role in the development and persistence of disease, in part by producing inflammatory cytokines. One of the major cytokines implicated in disease is interleukin-1β (IL-1β), which requires inflammasome activation. Much of the oral microbiome, including Streptococci, which are otherwise considered commensal, is required for the full development of periodontal disease. We have previously reported that inflammatory-activated macrophages and neutrophils counterintuitively allow survival of internalized Streptococcus gordonii over non-activated phagocytes. This internal bacterial survival leads to inflammasome activation via the cytoplasmic activator NLRP6, but not NLRP3, and subsequent increases in IL-1β release. Here, we test and find that the keystone pathogen Porphyromonas gingivalis can activate macrophages in a manner that allows for increased S. gordonii survival and IL-1β production above levels when P. gingivalis interacts with macrophages alone. We also use the mouse ligature-induced periodontal disease model to test the importance of NLRP6 in disease development. We found mice lacking NLRP6 had significantly reduced bone loss, IL-1β, and neutrophil infiltration following disease induced by P. gingivalis when S. gordonii or other mouse commensals were present, but had no effect when S. gordonii was inoculated alone. This work thus reveals an additional important inflammasome activation mechanism by which oral keystone pathogens may stimulate periodontal disease progression.
    DOI:  https://doi.org/10.1371/journal.ppat.1014574
  9. J Exp Med. 2026 Oct 05. pii: e20241620. [Epub ahead of print]223(10):
    Alox15 restrains glycolysis to support M2 macrophage effector function during helminth immunity.
    Dovran Ovezgeldiyev, Vanessa Trefzer, Rory Doolan, Mati Moyat, Gillian Coakley, Lakshanie C Wickramasinghe, Carmel Daunt, Beatrice Volpe, Fiona Henkel, Alex Serra, Maike Hartmann, Shirin Rezaei, Niki Ubags, Alana Butler, Roxanne Chatzis, Benjamin J Marsland, Adam Alexander T Smith, Deanna Deveson Lucas, Erin N S McGowan, Kathrina J Binger, Malcolm J McConville, Julia Esser-von Bieren, Nicola L Harris, Tiffany Bouchery.
      Macrophage polarization by type-2 cytokines is central to anti-helminth immunity and tissue repair. While some hallmark changes in macrophages are well-characterized and associated with protection against helminths, it is still unclear how macrophages exert their anti-helminth effects. In this context, we investigated arachidonate 15-lipoxygenase (LOX) (Alox15), a LOX well known for its role in macrophage polarization in the context of metabolic diseases, and a hallmark of type-2 macrophage (M2) human polarization. We show that in the absence of Alox15, M2 cannot trap and kill helminths. Surprisingly, expression of M2 markers was normal despite a loss of function. Instead, we found a concomitant increase in pro-inflammatory responses due to an uncontrolled activation of glycolysis. We further show that activation of Peroxisome proliferator-activated receptor-delta (PPAR-δ) by lipids downstream of docosapentaenoic acid (DPA) can restore normal glycolysis control, highlighting a novel role of lipids in the fine-tuning of the metabolic support required for optimal macrophage polarization.
    DOI:  https://doi.org/10.1084/jem.20241620
  10. Proc Natl Acad Sci U S A. 2026 Sep 22. 123(38): e2600693123
    Regulation of immune signal integration and memory by inflammation-induced chromosome conformation.
    Bence Daniel, Andy Y Chen, Katalin Sandor, Wenxi Zhang, Zhuang Miao, Kathryn E Yost, Caleb A Lareau, Howard Y Chang, Ansuman T Satpathy.
      Three-dimensional (3D) genome conformation is central to gene expression regulation, yet our understanding of its contribution to rapid transcriptional responses, signal integration, and memory in immune cells is limited. Here, we study the molecular regulation of the inflammatory response in primary macrophages using integrated transcriptomic, epigenomic, and chromosome conformation data, including base pair-resolution Micro Capture-C. We demonstrate that interleukin-4 (IL-4) primes the inflammatory response in macrophages by stably rewiring 3D genome conformation, juxtaposing endotoxin-, interferon-gamma-, and dexamethasone-responsive enhancers to their cognate gene promoters. CRISPR-based perturbations of enhancer-promoter contacts or CCCTC-binding factor (CTCF) boundary elements show that IL-4-driven conformation changes are required for enhanced and synergistic endotoxin-induced transcriptional responses, as well as transcriptional memory following stimulus removal. Moreover, transcriptional memory mediated by changes in chromosome conformation can occur in the absence of changes in chromatin accessibility or histone modifications. Collectively, these findings demonstrate that rapid and memory transcriptional responses to immunological stimuli are encoded in the 3D genome.
    Keywords:  3D genome; epigenome; innate immunity; memory
    DOI:  https://doi.org/10.1073/pnas.2600693123
  11. Nat Metab. 2026 Sep 15.
    Cysteine excess triggers a mitochondrial iron-dependent cell death.
    Toshitaka Nakamura, Ayaka Inoki, Nupur K Das, Brandon Chen, Artem Khan, Yuyang Liu, Beste Uygur, Frederick S Yen, Gokhan Unlu, Yatrik M Shah, Kıvanç Birsoy.
      Thiol-containing metabolites are central to cellular redox homeostasis1. Among these, cysteine functions as a proteogenic amino acid, supports redox balance and iron-sulfur cluster biogenesis, and, when depleted, triggers ferroptosis2. Cells nevertheless maintain cysteine at low levels, reflecting its intrinsic toxicity, but the mechanisms by which excess cysteine causes cell death remain unclear3. Here we performed a genome-wide CRISPR screen and identified mitochondrial iron transporters as essential mediators of cysteine toxicity. Limiting mitochondrial iron availability suppresses cysteine-induced cell death and prevents impairment of iron-sulfur cluster proteins and respiration. Mechanistically, cysteine mobilizes iron from ferritin, expands the cytosolic iron pool and drives mitochondrial iron accumulation. Enhancing glutathione reductase activity specifically within mitochondria restores redox balance downstream of iron accumulation and protects cells by maintaining iron-sulfur cluster integrity. Our findings suggest that maintaining low cysteine levels safeguards mitochondrial iron homeostasis, and that excess cysteine triggers a distinct mitochondrial iron-dependent cell death under conditions of thiol imbalance.
    DOI:  https://doi.org/10.1038/s42255-026-01616-7
  12. Sci Adv. 2026 Sep 18. 12(38): eaec0722
    A high-density CRISPR activation platform for mapping cancer dependencies and resistance pathways ex vivo and in vivo.
    Sarah T Diepstraten, Yexuan Deng, Margaret A Potts, Amy Heidersbach, Christina König, Kristel M Dorighi, Lin Tai, Andrew J Kueh, Lauren Whelan, Catherine Chang, Felix Brown, Gemma L Kelly, Jean-Philippe Fortin, Benjamin Haley, John E La Marca, Marco J Herold.
      CRISPR activation (CRISPRa) enables precise up-regulation of gene expression for ex vivo and in vivo applications. However, a lack of scalable, high-coverage tools has limited comprehensive genetic screening in murine models. Here, we introduce Partita, a next-generation mouse whole-genome CRISPRa sgRNA platform, designed for unparalleled efficiency in gene activation studies. Partita uses a high-density targeting strategy, deploying 10 sgRNAs per transcriptional start site, structured into five gene class-specific sublibraries to maximize transcriptional induction. To demonstrate the capabilities of Partita, we performed a series of large-scale screens: an in vitro enrichment/depletion screen, whole-genome CRISPRa screens in a double-hit lymphoma model to uncover resistance factors to proapoptotic drugs (venetoclax, nutlin-3a, and etoposide) and an in vivo screen to identify accelerators of MYC-driven lymphomagenesis. Each experiment revealed both expected and unexpected regulators, with high validation rates. By enabling robust gain-of-function screening, Partita unlocks new avenues for functional genomics and expands the toolkit for discovering key drivers of biological processes across diverse research fields.
    DOI:  https://doi.org/10.1126/sciadv.aec0722
  13. Cell. 2026 Sep 14. pii: S0092-8674(26)01004-4. [Epub ahead of print]
    Programmed ribosomal frameshifting triggers translational stress to promote viral replication.
    Audrey Xavier, Melinda Kolling, Ashley M Bourke, Thorsten Mosler, Cristian Prieto-Garcia, Emil Karaulanov, Michaela Reissland, Michel Tassetto, Damian Kim, Katleen Klaassen, Katharina Grikscheit, Emma Torbica, Verena Dederer, Jonas Busam, Rubina Kazi, Ruth Olmer, Srinivas Reddy Pallerla, Sebastian Mathea, Markus E Diefenbacher, Kathi Zarnack, Denisa Bojkova, Marek Widera, Ranen Aviner, Raul Andino, Sandra Ciesek, Ivan Dikic.
      Programmed ribosomal frameshifting (PRF) is a conserved viral strategy for expressing polyproteins from compact genomes. Although PRF is traditionally viewed as a structural mechanism, here we show that it functions as a regulatory signal that rewires host translation in favor of viral replication. A minimal SARS-CoV-2 PRF element is sufficient to activate the GCN2 arm of the integrated stress response (ISR) independently of the canonical ISR sensor ZAKα. This activation serves as a temporal switch during early infection to shut off host translation and is required for viral propagation in cells and human airway organoids. Proteomic and genetic screens identify DRG1 and IGF2BP3 as key mediators of PRF-induced GCN2 activation. We further show that this PRF-GCN2 axis is conserved in human immunodeficiency virus (HIV)-1 and West Nile virus, highlighting its broad relevance across RNA viruses. These findings reveal a sophisticated mechanism of viral translational control, highlighting PRF as a stress-inducing module that enhances viral replication.
    Keywords:  RNA virus; cellular stress; host-pathogen interactions; integrated stress response; programmed ribosomal frameshifting; ribosome collision; translation; virology
    DOI:  https://doi.org/10.1016/j.cell.2026.08.031
  14. Apoptosis. 2026 Sep 16. pii: 229. [Epub ahead of print]31(10):
    Lactylation and regulated cell death: the substrate defines the outcome.
    Shanjie Luan.
      
    DOI:  https://doi.org/10.1007/s10495-026-02445-5
  15. Nat Commun. 2026 Aug 14. pii: 9771. [Epub ahead of print]17(1):
    Evolutionary conservation analysis reveals a primordial function of STING as a regulator of lipid metabolism via FADS2.
    Soumyabrata Guha, Joanna Re, Stéphane Grégoire, Morgane Chemarin, Adeline Augereau, Yasmine Messaoud-Nacer, Pierre Le Hars, Hanane Chamma, Victoria Bergas, Collin McNairy, Jenny Nguyen, Jennifer Barrat, Jean-Paul Pais de Barros, Arielle Woznica, Niyazi Acar, Isabelle K Vila, Pierre Boudinot, Nadine Laguette.
      The stimulator of interferon genes (STING) is a pivotal regulator of type I interferon (IFN) responses. Although the IFN system is confined to vertebrates, STING is present across metazoans and in some unicellular eukaryotes, suggesting involvement in distinct functions prior to vertebrate divergence. Here we explore the conservation of STING-mediated regulation of polyunsaturated fatty acid (PUFA) metabolism. We find that STING homologs from vertebrates, invertebrates, and unicellular eukaryotes interact with fatty acid desaturase 2 (FADS2), the rate-limiting enzyme in PUFA metabolism, and influence subsequent functional outputs. Specifically, we show that STING homologs differentially shape cell susceptibility to infection by DNA and RNA viruses independently of the activation of IFN responses, suggesting that STING-mediated metabolic pathway regulation may participate in primitive host defense mechanisms. Thus, we identify STING-mediated metabolic regulation as an evolutionarily conserved feature and a primordial function of STING.
    DOI:  https://doi.org/10.1038/s41467-026-76833-5
  16. Nature. 2026 Sep 16.
    Mitochondrial fission factor senses and governs ferroptosis.
    Songjun Dai, Xiaoyan Dai, Tingting Zhang, Yuanyuan Qi, Xinquan Yang, Pengfei Diao, Chaodong Ge, Wenxiang Huang, Jisheng Ran, Xueliang Yang, Peng Zhang, Keke Zheng, Ruijun Wang, Hong Qian, Kunxiao Zhang, Junbing Wu, Caiyun Fu, Qian Ba, Junxia Min, Fudi Wang, Qiang Zhang.
      Ferroptosis is a form of regulated cell death driven by iron-dependent lipid peroxidation and is implicated in diverse pathological states1-4. Although mitochondria and other organelles are increasingly being recognized as important modulators of ferroptosis5-7, a unifying mechanism that couples organelle dynamics to ferroptotic execution has remained elusive. Here using quantitative phosphoproteomics, we identified mitochondrial fission factor (MFF) as a key ferroptosis-selective regulator. Mechanistically, the lipid mediator 17-HETE promotes phosphorylation of MFF at Ser155, which triggers the coordinated fragmentation and dysfunction of mitochondria and peroxisomes. This remodelling intensifies interorganelle crosstalk, amplifies oxidative stress and accelerates ferroptotic death. To monitor this phosphorylation event in living cells, we developed MFF-SPARK, a phase-separation-based biosensor, for real-time tracking of ferroptosis through MFF activation. Using MFF-SPARK, we identified PKCβ and DUSP22 as a coordinated kinase-phosphatase pair that governs MFF phosphorylation. We also discovered avermectin B1 as a pharmacological activator of the PKCβ-MFF axis, which can sensitize tumours to ferroptosis in vivo. Together, our findings establish MFF phosphorylation as a central regulatory node in ferroptosis-associated organelle remodelling and provide a conceptual framework and toolbox for monitoring and pharmacologically interrogating ferroptosis.
    DOI:  https://doi.org/10.1038/s41586-026-11020-6
  17. Nat Cell Biol. 2026 Sep 15.
    DFCP1-containing ER microdomains mediate lysosomal membrane repair.
    Maja Radulovic, Sascha Pust, Athanasios Kournoutis, Di Chen, M Isabel Giner, Qijian Liang, Santosh Phuyal, Thomas J Böddeker, Katy McCarron, Eric Herrmann, Kevin Rose, Sebastian W Schultz, Andreas Brech, James H Hurley, Claudio Bussi, Luis Bonet-Ponce, Maximiliano G Gutierrez, Camilla Raiborg, Harald Stenmark.
      Lysosomal membrane integrity is essential for preserving cellular homeostasis in response to different stressors. Upon lysosomal membrane permeabilization, cells activate several mechanisms for lysosomal membrane repair, including ESCRT proteins, phosphatidylinositol 4-phosphate (PI4P)-dependent lipid transfer from the endoplasmic reticulum (ER) and conjugation of ATG8 family proteins to single membranes (CASM). The interplay between these pathways and the regulation of the lipid transfer machinery remain incompletely understood. Here we show that phosphatidylinositol 3-phosphate (PI3P)-containing ER domains play a major role in lysosomal membrane repair. PI3P is formed on lysosome-proximal ER domains by the phosphatidylinositol 3-kinase PIK3C3/VPS34 in response to membrane damage, and inhibition or depletion of PIK3C3 inhibits lysosome repair. Mechanistically, the ATPase DFCP1/ZFYVE1 accumulates on lysosome-proximal ER domains by its PI3P binding, triggered by Ca2+ efflux from lysosomes and requiring the ULK1 kinase complex and ER proteins of the VAP family. Downstream of CASM, PI4P, ESCRTs and PI3P, DFCP1 promotes focal accumulation of the lipid channel VPS13C on ER domains proximal to damaged lysosomes to promote their repair. The function and dynamics of DFCP1 depend on its ability to bind and hydrolyse ATP, and absence of DFCP1 compromises cellular resistance to vacuolar damage induced by Listeria monocytogenes. We conclude that DFCP1 mediates concentration of the ER-associated lipid transport machinery at damaged lysosomes to promote their sealing in response to Ca2+ flux and PIK3C3 activation.
    DOI:  https://doi.org/10.1038/s41556-026-02062-z
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