bims-cediti 2026-07-05 papers

bims-cediti

Biomed News

on Cell death in innate immunity, inflammation, and tissue repair

Issue of 2026–07–05
twelve papers selected by
Kateryna Shkarina, Universität Bonn

Linear ubiquitin chain assembly complex contributes to NLRP3-mediated pyroptotic cell death.
Apoptosis as an evolutionary battleground: pathogen pressure and the shaping of programmed cell death pathways.
The centrosomal hub unifies regulatory factors of NLRP3 inflammasome activation.
Dual activation of NLRP3 and pyrin inflammasomes mediates host responses to the human fungal pathogen Coccidioides.
Cytokines driven by caspase-1 and RIPK3 are antagonistic.
Species-specific regulation of necroptosis by STK38-dependent RIPK1 phosphorylation.
Beyond the veil of cell death.
Autofluorescence enables detection and quantification of EETosis in human leukocyte cultures.
Distinct ATRX functions cooperate with 9-1-1 and CST complexes to safeguard replication and telomere integrity.
A Non-Canonical Role for Hepatocyte MLKL in Promoting Mitochondrial Dysfunction and Senescence in the Aging Liver.
A WEEV 6K viroporin activates MLKL-dependent necroptosis to drive inflammatory injury.
Penfluridol Triggers GSDME-Mediated Immunogenic Pyroptosis to Potentiate Antitumor Immunotherapy.

iScience. 2026 Jul 17. 29(7): 116448

Linear ubiquitin chain assembly complex contributes to NLRP3-mediated pyroptotic cell death.

Tiphaine Douanne, Rosalie Moreau, Valeria Trapani, Kilian Trillet, Hubert B Leloup, Virginie Petrilli, Julie Gavard, Nicolas Bidère.

  Activation of the NLRP3 inflammasome by infectious or sterile insults culminates in pyroptosis, a lytic and highly inflammatory form of programmed cell death. A safeguarded two-step process tightly regulates pyroptosis: priming, which drives NF-κB signaling, followed by execution, ultimately leading to plasma membrane rupture. Linear (Met1-linked) ubiquitination, catalyzed by the E3 ligase complex LUBAC, was previously shown to participate in pyroptosis, but the underlying mechanisms are not fully understood. In this study, we show that Met1-linked ubiquitin chains can assemble during both priming and execution phases, independently of the inflammasome sensor NLRP3. Genetic deletion of the LUBAC enzymes or pharmacological inhibition impairs pyroptosis. Conversely, cell death is enhanced without the deubiquitinase OTULIN, which selectively removes linear ubiquitination. Finally, using an optogenetic model to bypass priming, we demonstrate that Met-1-linked ubiquitination is required for the execution phase of pyroptosis. These findings offer insights into the regulation of pyroptotic cell death by linear ubiquitination.

Keywords:  molecular biology; molecular network

DOI:  https://doi.org/10.1016/j.isci.2026.116448
Front Cell Dev Biol. 2026 ;14 1800300

Apoptosis as an evolutionary battleground: pathogen pressure and the shaping of programmed cell death pathways.

Fiordaliso Carolina Román-Carraro, Laila Gutiérrez-Kobeh.

  Apoptosis is a tightly regulated form of programmed cell death that enables the controlled elimination of damaged or infected cells without eliciting deleterious inflammatory responses. Beyond its fundamental roles in embryogenesis, tissue homeostasis, and cellular turnover, the molecular architecture of apoptosis reflects deep evolutionary origins shaped by mitochondrial quality control, the emergence of intercellular communication, and immune surveillance mechanisms. Apoptotic signaling is initiated through three principal pathways, the extrinsic (death receptor-mediated), perforin/granzyme-mediated, and intrinsic (mitochondrial) pathways, which converge on caspase activation as the final execution step. Accumulating evidence indicates that persistent interactions with intracellular pathogens have profoundly influenced the evolution and diversification of these pathways. Viruses, bacteria, fungi, and protozoan parasites have independently evolved convergent strategies to suppress, delay, redirect, or exploit apoptosis by targeting conserved regulatory nodes, including mitochondrial outer membrane permeabilization, Bcl-2 family proteins, Bid-mediated pathway integration, Apaf-1-dependent caspase activation, and inhibitors of apoptosis proteins. These pathogen-driven pressures have not only shaped infection outcomes but have also contributed to the expansion, redundancy, and regulatory complexity of host apoptotic machinery. Here, we synthesize recent advances in the understanding of pathogen-mediated modulation of apoptosis and propose that programmed cell death operates as part of an integrated, evolutionarily conserved network of host defense. In this framework, apoptosis emerges as a central battleground in host-pathogen coevolution, linking cellular homeostasis to immune protection.

Keywords:  Bcl-2 family; apoptosis; caspases; coevolution; host–pathogen interactions; innate immunity; mitochondria; regulated cell death

DOI:  https://doi.org/10.3389/fcell.2026.1800300
Proc Natl Acad Sci U S A. 2026 Jul 07. 123(27): e2612800123

The centrosomal hub unifies regulatory factors of NLRP3 inflammasome activation.

Man Wu, Hao Wu.

  The NLRP3 inflammasome is central to host defense and sterile inflammation and forms condensates at the microtubule-organizing center (also known as the centrosome), although the mechanisms regulating this process remain unclear. Here we define a functional relationship among microtubule transport, the centrosomal kinase NEK7, priming, and NLRP3 abundance. We show that microtubule-dependent transport is required for NEK7-dependent NLRP3 activation and promotes NEK7 to the pericentriolar material (PCM). Microtubules, priming, and NEK7 synergistically converge on PCM abundance, thereby creating a permissive centrosomal environment for NLRP3 condensation and inflammasome assembly. Elevated NLRP3 expression compensates for limited PCM abundance, rendering K+ efflux-induced activation independent of both NEK7 and priming in human and mouse macrophages. By contrast, NLRP3 overexpression only partially bypasses NEK7 dependence in response to the K+ efflux-independent stimulus imiquimod, likely due to its activation of a non-trans-Golgi network pool of NLRP3 that is quantitatively limited. Together, these findings define a conserved spatial mechanism in which microtubule transport, NEK7 localization, priming, and NLRP3 abundance integrate at the PCM to establish the activation threshold and magnitude of NLRP3 inflammasome signaling across species and stimuli.

Keywords:  MTOC; NEK7; NLRP3 inflammasome; innate immunity; pericentriolar material

DOI:  https://doi.org/10.1073/pnas.2612800123
Nat Commun. 2026 Jul 01.

Dual activation of NLRP3 and pyrin inflammasomes mediates host responses to the human fungal pathogen Coccidioides.

Ka Pui Sharon Yau, Jonathan Rodrigo Erlich, Priscila Rodriguez, Sara McArdle, Cameron J Nowell, Matthew M Tate, Janset Onyuru, Ahalya Ratnavel, Aanika Desai, Jane Symington, Guillaume Castillon, Zbigniew Mikulski, Simon Goldstein, Aaron F Carlin, Joshua Fierer, Theo N Kirkland, Hal M Hoffman, Sinem Beyhan, Ben A Croker.

Coccidioides is a dimorphic fungal pathogen that grows as a mold in soil and produces infectious arthroconidia. Inhaled arthroconidia transition to spherules containing endospores in mammalian hosts. How distinct developmental forms of Coccidioides interact with immune cells remains poorly defined. Here, we show that arthroconidia activates TLR2 and induces NLRP3-pyrin inflammasomes in macrophages, while ferroptotic signaling promotes arthroconidia killing. Upon transition to spherules, only ruptured spherules-not intact ones-trigger IL-1β production through NLRP3-pyrin inflammasomes and GSDMD-GSDME pores. A TLR2-NLRP3-pyrin-IL-18 axis in macrophages promotes spherule growth. Endospores activate NLRP3 but not pyrin inflammasomes. Caspase-1-deficient mice show improved disease tolerance to coccidioidomycosis despite equivalent fungal burdens, correlating with enhanced neutrophil extracellular trap formation in lung granulomas. Neutrophils respond to spherules through NLRP3-pyrin inflammasomes, GSDMD-GSDME, and MLKL. Together, these findings reveal that Coccidioides morphotypes elicit distinct yet overlapping immune programs, coordinating inflammasome activation and regulated cell death to shape host-pathogen dynamics.

DOI: https://doi.org/10.1038/s41467-026-75022-8
bioRxiv. 2026 Jun 21. pii: 2026.06.19.733458. [Epub ahead of print]

Cytokines driven by caspase-1 and RIPK3 are antagonistic.

Lupeng Li, Jinyi Guo, Ying Wang, Carolyn A Lacey, Yaxin Liu, Yu-Ming Li, Jianxiang Peng, Heather N Larson, Melanie N Pratt, Bart Tummers, Douglas R Green, Edward A Miao.

Pyroptosis, apoptosis, and necroptosis are thought to provide redundant protection against intracellular pathogens. We found that mice lacking inflammasome signaling together with caspase-8 and MLKL were highly susceptible to infection by an environmental cytosol-invasive bacterium. Surprisingly, deletion of Ripk3 completely restored resistance despite the continued absence of all three cell death pathways. The outcome of the infection was determined not through cell death, but instead via the production of antagonistic cytokines arising from these pathways. Deleting Casp8 and Mlkl initiated an effector-triggered immunity-like response, in which RIPK3 induced type I interferons causing catastrophic susceptibility. Opposing this, caspase-1-dependent IL-1β production counteracted these type I interferons and restored resistance. Thus, susceptibility arose not from failure of regulated cell death, but from the activation of a RIPK3-driven type I interferons unopposed by caspase-1-driven IL-1β. Antagonistic cytokines embedded within cell death pathways, distinct from cell death itself, dictates the immune response to intracellular infection.

DOI: https://doi.org/10.64898/2026.06.19.733458
Cell Death Differ. 2026 Jul 01.

Species-specific regulation of necroptosis by STK38-dependent RIPK1 phosphorylation.

Seongmi Kim, Seung Ri Lee, Hyunjin Rho, Hye-Jung Kim, Hyuk Wan Ko, Donghyuk Shin, Seung-Mo Hong, Minjoong Kim, Jiyoung Yu, Kyunggon Kim, Joon-Yong Chung, Jaewhan Song.

Receptor-interacting protein kinase 1 (RIPK1) is a key stress sensor regulating cell death, inflammation, and tumorigenesis, yet how RIPK1 becomes activated remains unclear. Here, we identify serine/threonine kinase 38 (STK38) as a novel direct RIPK1 activator. STK38 binds to RIPK1, integrates into RIPK1-containing death complexes, and accelerates RIPK1-dependent cell death. STK38 deletion suppresses RIPK1-mediated necroptosis and apoptosis. Moreover, TNF-α stimulation triggers MEKK2-dependent STK38 activation, which in turn phosphorylates RIPK1 at serine 309, a residue conserved only in higher primates. This phosphorylation at S309 disrupts RIPK1's interaction with its inhibitory kinase MK2, thereby suppressing S320 phosphorylation and facilitating RIPK1 activation. Furthermore, colorectal cancer sample analysis revealed a positive correlation among STK38 expression, RIPK1 activation status, and favourable patient outcomes. Consistently, STK38 deficiency confers resistance to RIPK1-dependent cell death and facilitates tumour progression in a xenograft model. Our findings identify STK38 as an activator of RIPK1 and uncover a novel regulatory mechanism of RIPK1-mediated cell death in humans.

DOI: https://doi.org/10.1038/s41418-026-01795-6
Cell Chem Biol. 2026 Jul 01. pii: S2451-9456(26)00155-8. [Epub ahead of print]

Beyond the veil of cell death.

Douglas R Green, Greisly Nunez, Xiaoyu Zhang.

  Studies of regulated cell death have largely focused on the underlying mechanisms and modalities resulting in cell demise, as well as the biological and pathological consequences of cell death. More recently, at least some attention has turned to other questions: how do cells that engage a regulated cell death pathway sometimes survive? And do such "near-death experiences" alter the biology of the surviving cell? Like Alice passing through the looking glass, this 180° change in perspective may represent a paradigm shift in the field. Here, we discuss the concepts, mechanisms, and potential consequences of cell survival despite engaging a regulated cell death pathway.

Keywords:  apoptosis; drug-tolerant persister cells; ferroptosis; necroptosis; pyroptosis

DOI:  https://doi.org/10.1016/j.chembiol.2026.05.003
J Leukoc Biol. 2026 Jul 03. pii: qiag096. [Epub ahead of print]

Autofluorescence enables detection and quantification of EETosis in human leukocyte cultures.

Masashi Akiyama, Koichi Kokame.

  Eosinophils are leukocytes involved in defense against multicellular parasites and other pathogens. Like neutrophils, eosinophils can undergo a cytolytic form of cell death known as eosinophil extracellular trap cell death (EETosis), during which they release DNA and cytoplasmic granules to form eosinophil extracellular traps (EETs). Here, we demonstrate that eosinophil granules released during EETosis exhibit distinct autofluorescence in both purified human eosinophil cultures and mixed leukocyte cultures. This autofluorescence allowed detection of EETosis in mixed leukocyte cultures without additional staining or eosinophil isolation. We further show that two vanilloid compounds, previously identified as inhibitors of NETosis, suppress PMA-induced EETosis. By measuring the autofluorescence intensity of released eosinophil granules, we successfully quantified the inhibitory effects of these compounds on EETosis. Our autofluorescence-based assay enables rapid and convenient detection of EETosis and provides a useful tool for in vitro studies of eosinophil biology.

Keywords:  EETosis; autofluorescence; eosinophil; leukocyte culture; live-cell imaging; vanilloid

DOI:  https://doi.org/10.1093/jleuko/qiag096
Nat Struct Mol Biol. 2026 Jun 30.

Distinct ATRX functions cooperate with 9-1-1 and CST complexes to safeguard replication and telomere integrity.

Sandra Segura-Bayona, Marija Maric, Tohru Takaki, Zornitsa Manova, Tyler H Stanage, Aurora I Idilli, Shudong Li, Graeme Hewitt, Feras E Machour, Rhona Millar, Marek Adamowicz, Ronnie Ren Jie Low, Phil Ruis, Benura Azeroglu, Todd Fallesen, Harshil Patel, Steven Howell, Panagiotis Kotsantis, Michael Howell, Simon J Boulton.

Mutations in the ATRX chromatin remodeler confer a predisposition to a developmental genetic disorder and cancer, but how ATRX safeguards genome and telomere stability remains unresolved. Here, we uncover critical dependencies for the CTC1-STN1-TEN1 (CST) complex and RAD9A-HUS1-RAD1 (9-1-1) clamp in ATRX-deficient cells. ATRX-CST synthetic lethality manifests following accumulation of telomeric G-rich single-stranded DNA (ssDNA), which results in telomere loss and cell death. Conversely, we attribute ATRX-9-1-1 synthetic lethality to genome-wide ssDNA lesions, which compromise DNA replication. We further show that ATRX suppresses DNA damage during replication stress by counteracting the activity of the FAM111A protease. We demonstrate that roles of ATRX in telomere maintenance and replication are genetically separable, requiring its ATPase activity and PIP-box, respectively. We also show that such roles protecting genome stability are largely independent of the ATRX-DAXX interaction. Collectively, our data show that functions of ATRX in suppressing toxic ssDNA lesions are context-dependent and are key to global DNA replication and telomere integrity.

DOI: https://doi.org/10.1038/s41594-026-01827-2
Aging Cell. 2026 Jul;25(7): e70618

A Non-Canonical Role for Hepatocyte MLKL in Promoting Mitochondrial Dysfunction and Senescence in the Aging Liver.

Sabira Mohammed, Chao Jiang, Travis Pennington, Shylesh Bhaskaran, Phoebe Ohene-Marfo, Kara F Kneuper, Constantin Georgescu, Kamille Pitts, Albert Tran, Zongkai Peng, Amit Singh, Zhibo Yang, Tiangang Li, Bethany Hannafon, Courtney Houchen, Jonathan D Wren, Andriy Yabluchanskiy, Veronica Galvan, Nagib Ahsan, Michael Kinter, Tommy L Lewis, Sathyaseelan S Deepa.

  Liver aging is characterized by chronic inflammation and metabolic dysfunction that drive progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Necroptosis, a pro-inflammatory form of cell death via the Receptor-Interacting serine/threonine-Protein Kinase 1 (RIPK1)-RIPK3-Mixed Lineage kinase domain Like pseudokinase (MLKL) pathway, is activated in aging livers, and systemic inhibition of this pathway reduces hepatic inflammation and pathology. The cell type-specific role of necroptosis in liver aging, however, is unclear. Notably, RIPK3 is suppressed in hepatocytes under metabolic disease, suggesting necroptosis independent functions for MLKL. Here, we show that MLKL is elevated in aged hepatocytes and drives liver aging via a non-necroptotic mechanism. Using hepatocyte-specific MLKL-overexpressing mice (MLKLHepOE), we find that MLKL overexpression does not induce necroptosis but instead promotes cellular senescence, evidenced by increased p16INK4a and p21WAF1/Cip1 and elevated senescence associated secretory phenotype (SASP). Mechanistically, MLKL induces hepatocyte mitochondrial dysfunction, with impaired respiration, altered mitochondrial dynamics, and increased reactive oxygen species, implicating oxidative stress as a contributing mechanism. This mitochondrial stress is associated with enhanced release of pro-inflammatory extracellular vesicles (EVs) and induction of senescence in hepatocytes and non-parenchymal cells. While hepatocytes contribute substantially to total senescent burden by abundance, macrophages emerge as a senescence-enriched population, indicating amplification of senescence through non-cell-autonomous signaling. Collectively, these findings reveal a non-lethal, non-necroptotic function of hepatocyte MLKL in promoting liver inflammaging via mitochondrial dysfunction and paracrine senescence signaling, identifying MLKL as a regulator of hepatic aging and a potential therapeutic target in age-associated liver disease.

Keywords:  MLKL; aging; fission‐fusion; hepatocyte; liver; mitochondria; oxidative stress; senescence

DOI:  https://doi.org/10.1111/acel.70618
Cell Death Discov. 2026 Jul 02.

A WEEV 6K viroporin activates MLKL-dependent necroptosis to drive inflammatory injury.

Ziyan Zhou, Pengpeng Wu, Zhaobing Gao, Bingqing Xia.

Neurotropic alphavirus infection is characterized by neuronal injury and sustained neuroinflammation, yet the viral determinants linking membrane perturbation to host inflammatory damage remain poorly defined. Here, we show that the Western equine encephalitis virus (WEEV) 6K protein functions as an ER-localized viroporin, displaying stable single-channel activity with broad cation permeability. Consistent with its ion channel activity, 6K expression perturbs intracellular Ca²⁺ store homeostasis and is associated with cellular injury phenotypes. Mechanistically, 6K predominantly engages MLKL-mediated necroptosis, identifying programmed necrotic signaling as a principal pathway underlying 6K-driven injury under these conditions. Importantly, genetic deletion or pharmacological inhibition of MLKL significantly attenuates 6K-associated cellular damage and inflammatory release, establishing MLKL-dependent execution as a key modifiable node in viroporin-induced host injury. We further identify HYH09-D4 as a protective small molecule that dampens MLKL activation and limits tissue damage associated with 6K expression. Together, these findings define WEEV 6K as a host-facing viroporin that links ionic dysregulation to MLKL-dependent necroptosis and suggest that targeting MLKL may represent a broadly applicable strategy to mitigate host injury driven by 6K-encoding alphaviruses.

DOI: https://doi.org/10.1038/s41420-026-03229-1
Adv Sci (Weinh). 2026 Jul 03. e76408

Penfluridol Triggers GSDME-Mediated Immunogenic Pyroptosis to Potentiate Antitumor Immunotherapy.

Linfeng Li, Daishi Li, Danyao Chen, Yating Dian, Lei Yao, Hui Su, Ziyu Guo, Deze Zhao, Zihua Wu, Furong Zeng, Chunfang Zhang, Guangtong Deng.

  The potential of pyroptosis in antitumor immunity is well-established; however, its clinical translation is hindered by the lack of safe and effective pyroptosis inducers. Here, using a high-throughput screen of 240 antipsychotic agents approved by the Food and Drug Administration (FDA), we identify the antipsychotic agent penfluridol (PF) as a potent inducer of pyroptosis via a previously unreported molecular pathway. Mechanistically, PF directly binds to and inhibits TTI1, leading to activation of the TNFA signaling via NFKB and subsequent caspase-8/caspase-3-dependent cleavage of GSDME, culminating in pyroptotic cell death. Preclinically, PF not only exhibits monotherapy efficacy in immunocompetent hosts but also acts synergistically with anti-PD-1 therapy in both transplanted and spontaneous melanoma and HCC models without inducing systemic toxicity. Clinically, low TTI1 expression coupled with activated TNFA signaling via NFKB correlates with improved immunotherapy response and prolonged overall survival, suggesting its potential utility as a predictive biomarker. Collectively, our work establishes a compelling paradigm for repurposing pyroptosis inducers to stimulate antitumor immunity.

Keywords:  GSDME; PF; antipsychotic; anti‐PD‐1; immunotherapy; pyroptosis

DOI:  https://doi.org/10.1002/advs.76408