bims-cediti Biomed News
on Cell death in innate immunity, inflammation, and tissue repair
Issue of 2026–10–25
twelve papers selected by
Kateryna Shkarina, Universität Bonn
  1. BAK and BAX form a multiprotein complex to drive mtDNA efflux and caspase-independent cell death.
  2. The pyrin inflammasome senses OCTN2-mediated uptake of extracellular ʟ-carnitine from muscle injury or ingestion.
  3. Taurine lowers inflammaging by regulating the NLRP3 inflammasome in macrophages.
  4. Death receptors regulate entry to therapy-induced senescence and orchestrate addiction to IAPs.
  5. Long-term Nlrp3 gain-of-function mutation promotes cardiac dysfunction independent of inflammasome in mice.
  6. Microglial protein kinase CK2 prevents obesity in mice potentially through NLRP3 inflammasome activation.
  7. Metabolic hallmarks of regulated cell death.
  8. IRAK4 autophosphorylation functions as a molecular switch to regulate death domain assembly and Myddosome maturation.
  9. Short-term memory of past caspase activity biases cell elimination in vivo.
  10. Perforin triggers iron-induced mitochondrial damage to drive ferroptosis and anti-tumor immunity.
  11. Proteasome inhibition bidirectionally regulates ferroptosis sensitivity.
  12. Proximity biotinylation at the host-Shigella interface reveals UFMylation as an antibacterial pathway.
  1. Science. 2026 Oct 22. 394(6822): eaea2181
    BAK and BAX form a multiprotein complex to drive mtDNA efflux and caspase-independent cell death.
    Shaoyuan Yang, Hyungjin Kim, Guanghong Liao, Na Ta, Ho-Chou Tu, Shriram Ramani, Chih-Yu Chen, Zih-Yu Li, Nobuhiro Tanno, James J Hsieh, Emily H Cheng.
      The apoptotic regulators BAX and BAK, once activated, form homo-oligomers to trigger mitochondrial outer membrane permeabilization (MOMP), activating the apoptosome and caspases. Activation of BAX-BAK without apoptosome activation triggers sustained efflux of mitochondrial DNA (mtDNA) and caspase-independent cell death. However, the molecular basis of mtDNA efflux remains unclear. We purified a macromolecular complex comprising BAK, BAX, activator BH3-only molecules, voltage-dependent anion channels 1 and 2 (VDAC1 and VDAC2), and prohibitins that released mtDNA from mitoplasts. BAX-BAK activation resulted in VDAC closure, mitochondrial calcium influx, and mtDNA efflux. Loss of VDAC1, VDAC2, or prohibitins prevented BAX-BAK activation-induced mtDNA efflux and caspase-independent cell death without affecting MOMP or mitochondrial inner membrane herniation. These findings support differential regulation of cytochrome c and mtDNA efflux by distinct BAX-BAK complexes.
    DOI:  https://doi.org/10.1126/science.aea2181
  2. Cell. 2026 Oct 19. pii: S0092-8674(26)01117-7. [Epub ahead of print]
    The pyrin inflammasome senses OCTN2-mediated uptake of extracellular ʟ-carnitine from muscle injury or ingestion.
    Eric I Elliott, Tomomi M Yoshida, Susana C B R Nakandakari, Scott Pope, Cuiling Zhang, Timothy Nottoli, Jae Jin Chae, Daniel L Kastner, Richard A Flavell, Vishwa Deep Dixit, Vijay A Rathinam, Fayyaz S Sutterwala, Andrew Wang.
      Red-meat-containing diets are epidemiologically associated with diseases of chronic inflammation, while diets that restrict red meat improve health. Yet, it is uncertain how red meat incites inflammation. Here, we discover that ʟ-carnitine, an amino acid highly concentrated in skeletal muscle myocytes, drives inflammasome activation in lipopolysaccharide (LPS)-challenged mice and LPS-primed murine and human macrophages. We find that extracellular ʟ-carnitine represses mevalonate synthesis, thereby triggering activation of the pyrin inflammasome, downstream of cellular import by the high-affinity ʟ-carnitine transporter OCTN2. We find that the inflammatory response to skeletal muscle injury also requires pyrin and OCTN2. Thus, in summary, we identify macrophages as sentinels of exogenous and endogenous extracellular ʟ-carnitine that serve as a proxy for skeletal myocyte damage, and we open the field to examine the mechanistic basis for how excess dietary intake of carnitine-rich food drives inflammatory disease.
    Keywords:  ASC; MEFV; OCTN2; SLC22A5; caspase-1; inflammasome; interleukin-17a; interleukin-1β; pyrin; rhabdomyolysis; sepsis; ʟ-carnitine
    DOI:  https://doi.org/10.1016/j.cell.2026.09.015
  3. Cell. 2026 Oct 23. pii: S0092-8674(26)01207-9. [Epub ahead of print]
    Taurine lowers inflammaging by regulating the NLRP3 inflammasome in macrophages.
    Chenyang Guan, Seungjin Ryu, Mingze Dong, Yitao Zhu, Rae Maeda, Yun-Hee Youm, Subhasis Mohanty, Hee-Hoon Kim, Lucie Orliaguet, Tamara Dlugos, Steven R Smith, Eric Ravussin, Janset Onyuru, Hal M Hoffman, Stephan Siebel, Andrew Wang, Yaqiu Wang, Yuval Kluger, Albert C Shaw, Thirumala-Devi Kanneganti, Nathan LeBrasseur, Yuki Sugiura, Vishwa Deep Dixit.
      Whether a decline in taurine drives aging is debated, and despite high millimolar intracellular concentrations, its function as a potential guardian of cytosolic homeostasis is unclear. Here, we show that aging increases circulating taurine concentrations in humans and mice. Further elevating taurine in aged mice enhances health span, engaging anti-inflammatory pathways previously linked to youthfulness, and reduces mortality from sepsis and inflammasome-mediated inflammation, suggesting an enantiostatic response. Mechanistically, diverse NLRP3-specific "danger signals" induce taurine efflux from macrophages as a proximal step to activate the inflammasome and the resultant pyroptosis. Taurine restoration in macrophages prevents NLRP3-induced trans-Golgi network disassembly, thereby suppressing NLRP3 inflammasome activation. Conversely, lowering taurine biosynthesis combined with reduced bioavailability in macrophages exacerbated inflammasome activation. In humans, sustained caloric restriction elevates adipose tissue taurine and is accompanied by lower inflammation. Together, we identify taurine as an immunometabolic rheostat that links danger sensing to NLRP3 inflammasome activation, suggesting taurine-based strategies to alleviate inflammaging and inflammasomopathies.
    Keywords:  NLRP3; aging; antiinflammation; caloric restriction; immunometabolism; inflammaging; inflammasome; lifespan; taurine; taurine efflux
    DOI:  https://doi.org/10.1016/j.cell.2026.09.061
  4. Sci Adv. 2026 Oct 23. 12(43): eaed4541
    Death receptors regulate entry to therapy-induced senescence and orchestrate addiction to IAPs.
    Gokhan Gunay, Seren Hamsici, Vaishnavi Venugopalan, Aoife Costigan, Melanie Fritsch, Aislinn Gallagher Aldave, Anne Huber, Brianna Fernandez, Hande Efe-Cicek, Pavel Davidovich, Pavitha Parathan, Akash Srivaths, Natalie Hudson, Eleanor Noone, Jeffrey O'Callaghan, Lisa A Mielke, Sarah L Doyle, Sabrina L Spencer, Matthew Campbell, Conor J Kearney, Hamid Kashkar, Seamus J Martin.
      Cytotoxic chemotherapy typically results in the elimination of a fraction of the tumor with surviving cells entering a state of persistence or premature replicative senescence that can lead to recurrence. Here, we show that therapy-induced senescence is associated with robust up-regulation of Fas and/or TRAIL-R2/DR5 death receptors in vitro and in vivo. The latter receptors restricted entry to senescence and exerted selective pressure on senescent cells through promoting assembly of proapoptotic receptor-interacting protein kinase 1 (RIPK1)/Fas-associated death domain protein (FADD)/Caspase-8 "FADDosome" complexes, restrained by cFLIPL. Accordingly, deletion of CASP-8 robustly enhanced entry to senescence and prolonged the life span of senescent cells. cIAP-2, which inhibits death receptor-driven cell death, was also up-regulated in senescent cells, and deletion of IAPs suppressed entry to senescence. Consistent with this, small-molecule IAP antagonists exhibited potent senolytic activity through enhancing death receptor-initiated Caspase-8 activation. Thus, death receptor-driven assembly of RIPK1/FADD/Caspase-8 complexes in senescent cells orchestrates addiction to IAPs that can be exploited by IAP antagonists.
    DOI:  https://doi.org/10.1126/sciadv.aed4541
  5. J Immunol. 2026 Oct 01. pii: vkag257. [Epub ahead of print]215(10):
    Long-term Nlrp3 gain-of-function mutation promotes cardiac dysfunction independent of inflammasome in mice.
    Mie Kurata, Kayo Takahashi, Naoe Kaneko, Kenji Kameda, Takanori Nakamura, Sho Hosokawa, Kasumi Murakami, Hideki Ogura, Satoshi Ishido, Osamu Yamaguchi, Junya Masumoto.
      Cryopyrin-associated periodic syndrome (CAPS) is an autoinflammatory disease caused by gain-of-function mutations in human nucleotide-binding domain, leucine-rich repeat-containing protein 3 (NLRP3), which lead to constitutive inflammasome activation and excessive IL-1β secretion. Long-term IL-1 blockade has markedly improved patient outcomes by preventing systemic inflammation and amyloidosis. However, whether chronic NLRP3 mutation exerts inflammasome-independent effects on the cardiac function remains unknown. We generated Nlrp3C257Y/WT knock-in mice as a novel CAPS model. Long-term survival, systemic inflammation, and cardiac function were assessed by biochemical, histological, and echocardiographic analyses. To determine inflammasome dependency, Nlrp3C257Y/WT mice were crossed with Asc-/- mice to generate double-mutant Nlrp3C257Y/WT × Asc-/- offspring. Nlrp3C257Y/WT mice exhibited early-onset cutaneous inflammation that gradually subsided, these mice developed marked left ventricular (LV) dilatation and mild systolic dysfunction after approximately 6 mo of age. Histological analysis revealed interstitial myocardial fibrosis in Nlrp3C257Y/WT mice. This result indicates that Nlrp3C257Y/WT mutation, which operates as a gain-of-function variant for inflammasome activation, impairs cardiac function largely driven by an inflammasome-dependent mechanism. In contrast, Nlrp3C257Y/WT × Asc-/- mice exhibited marked resolution of systemic inflammation; nevertheless, LV dilatation and reduced fractional shortening persisted. Long-term Nlrp3C257Y/WT mutation can lead to persistent cardiac dysfunction not only through inflammasome activation but also via inflammasome-independent mechanisms. Our findings reveal previously unrecognized inflammasome-independent mechanisms linking NLRP3 signaling to cardiac dysfunction. This study expands knowledge of the pathophysiological spectrum of CAPS and highlights inflammasome-independent NLRP3 signaling as a potential therapeutic target to prevent chronic cardiac complications in patients with CAPS and NLRP3-associated disorders.
    Keywords:  IL-1β; NLRP3 inflammasome; NLRP3 mutation; cardiac dysfunction; cryopyrin-associated periodic syndrome (CAPS)
    DOI:  https://doi.org/10.1093/jimmun/vkag257
  6. Nat Commun. 2026 09 22. pii: 11019. [Epub ahead of print]17(1):
    Microglial protein kinase CK2 prevents obesity in mice potentially through NLRP3 inflammasome activation.
    Ji-Won Lee, Nayoun Kim, Seolsong Kim, Seokjae Park, Hyeri Nam, Younghwan Lee, Seohyeon Hwang, Yeim Lee, Sehee Ha, Wonkeon Koo, Eun-Kyoung Kim, Seong-Woon Yu.
      Protein kinase CK2 plays an important role in the regulation of metabolism and obesity. However, the metabolic role of CK2 and its substrates in the brain remain largely unknown. Here, we show that microglial CK2 is required for metabolic homeostasis through ASC phosphorylation and subsequent NLRP3 inflammasome-mediated interleukin (IL)-18 maturation and release. Mice with microglia-specific, inducible deletion of CK2 regulatory subunit β (CK2β) showed obese phenotypes with weight gain, abnormal glucose homeostasis, and decreased energy expenditure. At the molecular level, CK2 phosphorylated ASC at T154, and this phosphorylation was essential for ASC aggregation and NLRP3 inflammasome activation. Microglial deletion of CK2β decreased central production of IL-18, mirroring the obese phenotypes of mice lacking IL-18 signaling. Our results suggest that the microglial CK2-ASC-NLRP3 axis underlies the central regulation of metabolic homeostasis and prevents obesity through processing and secretion of IL-18. Nevertheless, a gap remains between these molecular mechanistic findings and the observed in vivo behavioral and metabolic phenotypes, highlighting the need for future systems-level analyses to fully delineate the broader substrate landscape of CK2 and to integrate the functional outcomes of CK2 deficiency in microglia with in vivo phenotypes.
    DOI:  https://doi.org/10.1038/s41467-026-77895-1
  7. Cell Res. 2026 Oct 20.
    Metabolic hallmarks of regulated cell death.
    Rui Kang, Xin Chen, Guido Kroemer, Daolin Tang.
      Regulated cell death (RCD) is characterized by distinct molecular execution mechanisms, but its initiation, progression, and biological consequences are increasingly recognized as being shaped by cellular metabolism. Bioenergetic state, redox homeostasis, nutrient availability, metal ion metabolism, inflammatory metabolism, and organelle function collectively determine cellular susceptibility to death and influence the activation and execution of diverse RCD programs. In this review, we synthesize the metabolic hallmarks of established, independently validated, and recently proposed forms of RCD, highlighting both their mechanistic diversity and their extensive metabolic convergence. We then examine the endogenous mechanisms that maintain metabolic homeostasis and discuss how their disruption reshapes cell death responses in human disease and therapeutic contexts. Together, these insights provide a guide to  the metabolic landscape of RCD and reveal metabolism not only as a modifier of cell death, but as a fundamental determinant of when, how, and with what consequences cells die. We conclude by discussing key conceptual and mechanistic challenges and emerging opportunities for therapeutically exploiting the metabolic control of RCD.
    DOI:  https://doi.org/10.1038/s41422-026-01306-9
  8. Nat Commun. 2026 10 21. pii: 11001. [Epub ahead of print]17(1):
    IRAK4 autophosphorylation functions as a molecular switch to regulate death domain assembly and Myddosome maturation.
    Niranjan A Srikanth, Rafael Deliz-Aguirre, Deepika Kumari Gola, Margaux Bilay, Elke Ziska, Ian R Kelsall, Yogesh Kulathu, Marcus J Taylor.
      The organization of signaling proteins into multi-component complexes is essential for innate immune responses and is often achieved through the oligomerization of death domains (DDs). The Myddosome, composed of MyD88 and IRAK family kinases, exemplifies this mechanism. However, how DDs assemble in an ordered and regulated manner to form Myddosomes to control signaling output remains unclear. Here, we show that IRAK4 kinase activity and autophosphorylation are required for IRAK4:IRAK1 heterotypic DD interactions. We show that IRAK1 is autoinhibited by its kinase domain, and IRAK4 phosphorylation relieves this inhibition, enabling IRAK1 DD incorporation into Myddosomes. This phosphorylation-dependent switch similarly controls IRAK2/3 incorporation. Thus, IRAK4 autophosphorylation acts as an energy-dependent molecular switch that integrates phosphorylation with protein oligomerization to drive Myddosome maturation and signal transduction. This mechanism demonstrates how enzymatic activity can impose temporal and spatial control over macromolecular assembly to ensure directional and context-dependent inflammatory signaling.
    DOI:  https://doi.org/10.1038/s41467-026-78773-6
  9. Nat Commun. 2026 09 22. pii: 11031. [Epub ahead of print]17(1):
    Short-term memory of past caspase activity biases cell elimination in vivo.
    Tom Cumming, Alexis Villars, Anđela Davidović, Florence Levillayer, Léo Valon, Romain Levayer.
      Apoptosis is triggered by the activation of Caspases leading to irreversible engagement in cell death. However, recent data outline numerous non-apoptotic functions of caspases as well as quite ubiquitous sublethal activation of effector caspases in vivo, opening the question of what drives the bifurcation between cell death and survival. Using quantitative live imaging combined with machine learning and optogenetics in the Drosophila pupal notum (a single-layer epithelium), we reveal the existence of a large heterogeneity of caspase activity thresholds between cells and distinct spatial domains with low or high sensitivity to caspases. We outline the central role of past exposure to sublethal caspase activity, which sensitises cells to apoptosis for several hours and reduces their threshold, and can bias single-cell elimination. Altogether, this work reveals the role of a cell's past history for apoptosis regulation in vivo, which can bias clonal selection and the spatial pattern of cell death.
    DOI:  https://doi.org/10.1038/s41467-026-77685-9
  10. Cell. 2026 Oct 23. pii: S0092-8674(26)01208-0. [Epub ahead of print]
    Perforin triggers iron-induced mitochondrial damage to drive ferroptosis and anti-tumor immunity.
    Hannah N Bell, Kavya Nair, Kole Tison, Peng Liao, Hongwei Lei, Marwa O El-Derany, Ayijiang Yisimayi, Haiwei Zhang, Ryan Rebernick, Weichao Wang, Yoshitaka Adachi, Cristina Castillo, Nupur K Das, Jinsu An, Vivien R Sutton, Xun Lin, Heng Lin, Xinghao Wang, Yunfei Li, Linda Vatan, Amr Aboud, Shuang Wei, Miguel Gijon, Samantha Goodwin, Yatrik M Shah, Ilona Kryczek, Joseph A Trapani, Margarida Barroso, Judy Lieberman, Weiping Zou.
      Cytotoxic CD8+ T cells and natural killer cells are critical effectors of anti-tumor immunity. Cytotoxic lymphocytes eliminate tumor cells by releasing perforin (Prf1), a pore-forming protein that enables granzymes (Gzms) to enter target cells and trigger both caspase-dependent and -independent cell death. Here, we uncover a previously unrecognized, Gzm-independent function of Prf1. We find that Prf1 directly induces tumoral ferroptosis, an iron- and lipid-dependent form of cell death. Mechanistically, Prf1-mediated pore formation drives endocytosis of the transferrin receptor, which increases cellular iron uptake. Prf1 promotes the formation of endosomal-mitochondrial contacts, which leads to mitochondrial iron accumulation, mitochondrial dysfunction, and tumor cell ferroptosis. Dietary iron supplementation suppresses tumor progression in murine tumor models in a Prf1-dependent manner. Higher Prf1 expression correlates with improved survival and enhanced response to immune checkpoint blockade in patients with cancer. These findings define a Gzm-independent function of Prf1 as a direct executioner of cancer cell death through ferroptosis.
    Keywords:  NK cell; T cell; ferroptosis; granzyme; immune checkpoint blockade; iron; mitochondria; perforin
    DOI:  https://doi.org/10.1016/j.cell.2026.09.062
  11. Cell Chem Biol. 2026 Oct 21. pii: S2451-9456(26)00369-7. [Epub ahead of print]
    Proteasome inhibition bidirectionally regulates ferroptosis sensitivity.
    Magdalena B Murray, Rishi Upadhyay, Krystina J Szylo, Aastha Gautam, Judith Goncalves, Giovanni Forcina, Ananya Vinayak, Onn Brandman, Scott J Dixon.
      Ferroptosis is a non-apoptotic cell death mechanism whose fundamental regulation continues to be elucidated. The proteasome is an essential multiprotein complex important for protein turnover. How proteasome function regulates ferroptosis is difficult to study given that proteasome inhibition causes apoptosis. Here, we isolated the effects of proteasome inhibition on ferroptosis by combining small molecule cell death inducers, pathway-specific cell death inhibitors, and direct cell death imaging. We find that proteasome inhibition enhances sensitivity to ferroptosis induced by glutathione peroxidase 4 (GPX4) inhibition while simultaneously promoting resistance to ferroptosis induced by system xc- inhibition. Sensitization to GPX4 inhibition requires protein synthesis but not the apoptosis execution machinery and is opposed by the activating transcription factor 4 (ATF4) stress response pathway. These findings establish proteasome-mediated protein turnover as a context-dependent regulator of ferroptosis and identify protein synthesis and ATF4 as key determinants of GPX4 inhibitor sensitivity.
    Keywords:  ATF4; Necrosis; cancer; iron metabolism; lipid peroxidation; oxidative stress; protein synthesis; ubiquitination
    DOI:  https://doi.org/10.1016/j.chembiol.2026.09.020
  12. Nat Commun. 2026 09 17. pii: 10930. [Epub ahead of print]17(1):
    Proximity biotinylation at the host-Shigella interface reveals UFMylation as an antibacterial pathway.
    Ana T López-Jiménez, Fabien Théry, Kathryn Wright, Hannah Painter, Shelby T Hoffmeister, Lucas Jarche, Jeremy Benjamin, Gerbrand J van der Heden van Noort, Dominik Brokatzky, Margarida C Gomes, Sydney L Miles, Damián Lobato-Márquez, Eva-Maria Frickel, John Rohde, Jonathan N Pruneda, Francis Impens, Serge Mostowy.
      Host cells contest invasion by intracellular bacterial pathogens with multiple strategies that recognise and/or damage the bacterial surface. To identify host defence factors targeted to intracellular bacteria, we developed a proximity biotinylation approach coupled to quantitative mass spectrometry that maps the host-bacterial interface during infection. Using this method, we discovered that intracellular Shigella and Salmonella become targeted by UFM1-protein ligase 1 (UFL1), an E3 ligase that catalyses the covalent attachment of Ubiquitin-fold modifier 1 (UFM1) to target substrates in a process called UFMylation. Shigella antagonises UFMylation in a dual manner: first, using its lipopolysaccharide to shield from UFL1 recruitment; second, preventing UFM1 decoration by the bacterial effector IpaH9.8. Absence of UFMylation leads to an increase of bacterial burden in human cells and zebrafish larvae. Contrary to ubiquitylation, the protective role of UFMylation is independent of autophagy. Altogether, our proximity mapping of the host-bacterial interface identifies UFMylation as an ancient antibacterial pathway and holds great promise to reveal other cell-autonomous immunity mechanisms.
    DOI:  https://doi.org/10.1038/s41467-026-77860-y
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