bims-cediti 2026-01-18 papers

bims-cediti

Biomed News

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

Issue of 2026–01–18
eleven papers selected by
Kateryna Shkarina, Universität Bonn

Dual NLRC4 and non-canonical inflammasome signaling drives human GSDMD-mediated killing of Shigella flexneri independently of bacterial cardiolipin.
Shigella OspF blocks rapid p38-dependent priming of the NAIP-NLRC4 inflammasome.
Redefining Shiga toxin-induced human cell death as NLRP1- and gasdermin E-mediated pyroptosis.
Activation of RIPK3 drives PANoptosis in human cells and inflammatory apoptosis in canine cells dependent on RIPK1, FADD and caspases.
De novo discovery of bicyclic cysteine-rich peptides targeting gasdermin D.
Cytokine storm.
Mitochondrial ligase MAPL drives pyroptotic cell death.
Advances in the research of gasdermin-dependent pyroptosis mechanisms and therapeutic targets in inflammatory diseases.
Nucleotide metabolic rewiring enables NLRP3 inflammasome hyperactivation in obesity.
Cellular consequences, citrullination substrates, and antigenicity resulting from wild-type and targeted PAD4 on cell surfaces.
METTL3-mediated m6A on nascent RNA coordinates translational and transcriptional programs to activate the NLRP3 inflammasome in macrophages.

bioRxiv. 2026 Jan 11. pii: 2026.01.11.698901. [Epub ahead of print]

Dual NLRC4 and non-canonical inflammasome signaling drives human GSDMD-mediated killing of Shigella flexneri independently of bacterial cardiolipin.

Mateusz Szczerba, Marcia B Goldberg.

Macrophages internalize and kill bacteria and thus are crucial for clearing bacterial infections. Although macrophage killing of some intracellular bacteria requires inflammasomes, the specific mechanisms of inflammasome-dependent killing are incompletely understood. Here we show that, upon infection with an intracellular pathogen Shigella flexneri , human macrophages activate a robust NLRC4-caspase-1 inflammasome response that restricts intracellular bacterial replication independently of pyroptosis. Gasdermin D (GSDMD) cleavage is required for bactericidal activity, revealing a GSDMD-dependent mechanism of bacterial killing independent of host cell death. We find that GSDMD-mediated killing of S. flexneri does not require bacterial cardiolipin, identifying a cardiolipin-independent mode of bacterial targeting. Priming macrophages with interferon (IFN)-γ enhances killing of intracellular S. flexneri by promoting involvement of caspase-4, which cooperates with caspase-1 to potentiate GSDMD function. These results identify a dual engagement of canonical and non-canonical inflammasomes that leads to macrophage killing S. flexneri while preserving host cell integrity. Furthermore, these findings uncover a previously unrecognized cardiolipin-independent mechanism of GSDMD-mediated bacterial killing with broad implications for immune cell control of cytosolic bacterial pathogens.

DOI: https://doi.org/10.64898/2026.01.11.698901
Proc Natl Acad Sci U S A. 2026 Jan 20. 123(3): e2510950123

Shigella OspF blocks rapid p38-dependent priming of the NAIP-NLRC4 inflammasome.

Elizabeth A Turcotte, Kyungsub Kim, Kevin D Eislmayr, Lisa Goers, Patrick S Mitchell, Cammie F Lesser, Russell E Vance.

  The NAIP-NLRC4 inflammasome senses pathogenic bacteria by recognizing the cytosolic presence of bacterial proteins such as flagellin and type III secretion system (T3SS) subunits. In mice, the NAIP-NLRC4 inflammasome provides robust protection against bacterial pathogens that infect intestinal epithelial cells, including the gastrointestinal pathogen Shigella flexneri. By contrast, humans are highly susceptible to Shigella, despite the ability of human NAIP-NLRC4 to robustly detect Shigella T3SS proteins. Why the NAIP-NLRC4 inflammasome protects mice but not humans against Shigella infection remains unclear. We previously found that human THP-1 cells infected with Shigella lose responsiveness to NAIP-NLRC4 stimuli, while retaining sensitivity to other inflammasome agonists. Using mT3Sf, a "minimal Shigella" system, to express individual secreted Shigella effector proteins, we found that the OspF effector specifically suppresses NAIP-NLRC4-dependent cell death during infection. OspF was previously characterized as a phosphothreonine lyase that inactivates p38 and ERK MAP kinases. We found that p38 was critical for rapid priming of NAIP-NLRC4 activity, particularly in cells with low NAIP-NLRC4 expression. Overall, our results provide a mechanism by which Shigella evades inflammasome activation in humans, and describe a mechanism for rapid priming of the NAIP-NLRC4 inflammasome.

Keywords:  Shigella; effector; inflammasomes

DOI:  https://doi.org/10.1073/pnas.2510950123
Proc Natl Acad Sci U S A. 2026 Jan 20. 123(3): e2510274123

Redefining Shiga toxin-induced human cell death as NLRP1- and gasdermin E-mediated pyroptosis.

Rafael Ricci-Azevedo, Bishajit Sarkar, Sonia Shivcharan, Aadrita Hazra, Mercy Browne, Emma K Carlson, Udayan Chidambaram, Vijay A Rathinam, Sivapriya Kailasan Vanaja.

  Shiga toxin (Stx)-mediated hemolytic uremic syndrome (HUS) prevails as the leading cause of pediatric renal failure worldwide despite decades of efforts to develop therapeutic strategies. Stx killing of large populations of sensitive cells in the vasculature and kidney underlies HUS development. However, the exact nature of Stx-induced cell death and its mechanism are not clear. Here, we demonstrate that Stx-induced cell death in several HUS-relevant human cells, such as kidney epithelial cells, podocytes, and human intestinal microvascular endothelial cells, is pyroptosis, an inflammatory form of cell death. Remarkably, our findings identify gasdermin E (GSDME) activation as the cardinal event that mediates Stx killing of human cells. Mechanistically, Stx activates, through ribotoxic stress, a caspase-8-caspase-3 pathway that licenses GSDME-dependent pyroptosis of susceptible cells. Intriguingly, NLRP1 amplifies this pyroptotic pathway in certain Stx-sensitive cells by promoting caspase-8 activation. Together, our findings define the nature and mechanism of a bacterial toxin-induced cell death, providing crucial insights into pathogenic determinants of a critical pediatric illness.

Keywords:  EHEC; Enterohemorrhagic E. coli; Gasdermin E; Shiga toxin; pyroptosis

DOI:  https://doi.org/10.1073/pnas.2510274123
Apoptosis. 2026 Jan 12. 31(1): 40

Activation of RIPK3 drives PANoptosis in human cells and inflammatory apoptosis in canine cells dependent on RIPK1, FADD and caspases.

Sarah M Worfolk, Noah J Phippen, Shayla G Verburg, Katrina A Kobal, Nicholas C Langelaan, Davier G Gongora, Jennifer Geddes-McAlister, Sarah K Wootton, Matthew S Miller, Samuel T Workenhe.

  Programmed cell death in animal species of the order Carnivora is suspected to be unique due to the potential defects in activating the lytic cell death pathways, necroptosis and pyroptosis. In a wide range of species of the order Carnivora, including domestic cats and dogs, racoons, red foxes, and ferrets, the absence of the necroptosis executioner protein MLKL (mixed-lineage kinase domain-like pseudokinase) is suspected to prohibit necroptotic lysis. It remains unclear what type(s) of cell death are activated in canine cells downstream of RIPK3 (receptor-interacting protein kinase 3). Here, we show that activation of RIPK3 by expressing it with a trimerization domain drives PANoptosis in human fibroblasts but activates apoptosis in canine epithelial cells. Expression of trimerizable canine and human RIPK3 in canine cells activated apoptotic cell death dependent on caspases, FAS-associated death domain protein (FADD), and RIPK1. Human RIPK3 in canine cells activated a rapid apoptosis compared to the canine version. Unlike canonical caspase 8 driven apoptosis, RIPK3-driven canine cell apoptosis is associated with the secretion of danger-associated molecular patterns (DAMPs) and pro-inflammatory cytokines. This is the first study defining the function of canine RIPK3 and potentially immunostimulatory, non-lytic, cell death in canine cells. This form of cell death can be further developed to ignite immunity against virus infections and cancer.

Keywords:  Apoptosis; Cell death; Dog; Necroptosis

DOI:  https://doi.org/10.1007/s10495-025-02241-7
Proc Natl Acad Sci U S A. 2026 Jan 20. 123(3): e2516051123

De novo discovery of bicyclic cysteine-rich peptides targeting gasdermin D.

Choi Yi Li, Yin Sun, Alexander A Vinogradov, Hiroaki Suga.

  Gasdermin D (GSDMD) is the principal executor of pyroptosis, a form of proinflammatory programmed cell death misregulation of which is associated with numerous diseases. Despite significant interest, no specific GSDMD inhibitors have been developed for clinical use so far. Here, we developed a strategy to generate mRNA-displayed libraries of bicyclic cysteine-rich peptides (bCRP), and utilized these libraries to develop potent peptide ligands to full-length GSDMD using a two-stage discovery process. Initial hit compounds were de novo discovered from GSDMD affinity selections using Random Nonstandard Peptides Integrated Discovery system, and were then optimized using mRNA display-based saturation mutagenesis. The resulting bCRPs bound to full-length GSDMD (best KD = 125 nM) and stabilized it against cleavage by caspase proteases. The bCRPs prevented the pore formation in liposome leakage assays and inhibited the secretion of IL-1β and lactate dehydrogenase from pyroptotic THP-1 cells. The potency, high metabolic stability, and synthetic accessibility of the discovered compounds make them promising leads for the development of GSDMD-targeting therapeutics.

Keywords:  Gasdermin D; bicyclic peptides; drug discovery; mRNA display; pyroptosis

DOI:  https://doi.org/10.1073/pnas.2516051123
Nat Rev Dis Primers. 2026 Jan 15. 12(1): 1

Cytokine storm.

Rajendra Karki, Mihai G Netea, Caroline Diorio, Thirumala-Devi Kanneganti.

Cytokine storm describes a spectrum of clinical manifestations that feature increased cytokine levels in circulation owing to overactivated immune responses. These increased concentrations of cytokines can cause tissue and organ damage, potentially leading to lethality. Cytokine storm can be induced by a variety of underlying clinical conditions, including infection, auto-inflammatory and autoimmune conditions, monogenic causes, or therapeutic intervention, which often makes diagnosis and treatment difficult. However, studies have identified conserved molecular mechanisms that inform therapeutic strategies. Cytokine storm is initiated by cytokine production and exacerbated by a self-amplifying positive feedback loop between cytokines and inflammatory cell death (PANoptosis). The process begins when cells detect triggers and undergo inflammatory signalling to produce and release cytokines via canonical secretion pathways or through lytic cell death such as pyroptosis and PANoptosis. This release of inflammatory cytokines, and potentially of other damage-associated molecules, can then drive inflammation and cell death in neighbouring cells through paracrine PANoptosis, resulting in further cytokine release and the amplification of the cycle. Improved understanding of the molecular and cellular mechanisms driving cytokine storm is critical for developing effective therapeutic strategies and improving clinical outcomes.

DOI: https://doi.org/10.1038/s41572-025-00677-4
Nat Struct Mol Biol. 2026 Jan 15.

Mitochondrial ligase MAPL drives pyroptotic cell death.

Yue Feng.

DOI: https://doi.org/10.1038/s41594-025-01735-x
Apoptosis. 2026 Jan 12. 31(1): 38

Advances in the research of gasdermin-dependent pyroptosis mechanisms and therapeutic targets in inflammatory diseases.

Chuanyu Shen, Yiming Zhang, Chuqiao Wei, Hanchi Wang, Yanmin Zhou.

  Inflammation, especially invasive bacterial inflammation, has always been a hot topic in medical research. With the emergence of superbugs and highly virulent viruses, current treatment methods are gradually revealing areas of deficiency. As an inflammatory form of cell death, the concept of pyroptosis offers new possibilities for the treatment of inflammation. Pyroptosis is typically triggered by inflammasomes and executed by the Gasdermin (GSDM) family. It is characterized by membrane perforation, cell swelling, and the release of cellular contents such as pro-inflammatory factors. Pyroptosis plays a crucial role in host immune defense, inflammatory diseases, and tumor regulation. In this review, we comprehensively explored each member of the GSDM family and its activation pathways, reviewed the cellular consequences of GSDM activation, and the role of GSDM-mediated pyroptosis in inflammatory diseases such as sepsis. We also provided a detailed account of the latest advancements in inflammation control targeting GSDM, aiming to offer new perspectives for precise therapies targeting pyroptosis.

Keywords:  Gasdermin; Inflammation; Non-proteolytic mechanism; Pyroptosis; Sepsis

DOI:  https://doi.org/10.1007/s10495-025-02250-6
Science. 2026 Jan 15. 391(6782): eadq9006

Nucleotide metabolic rewiring enables NLRP3 inflammasome hyperactivation in obesity.

Danhui Liu, Chuanli Zhou, Xiaochen Wang, Zhou Luo, Ruiyao Xu, Shanshan Huo, Lina Guo, Xuemei Luo, Shuhan Yang, Arielle Click, Janiece Vancil, Paola Barajas, Victor Mijares, Hamid Baniasadi, Nan Yan, Jan Rehwinkel, Dustin C Hancks, Elizabeth H Chen, Shuang Liang, Zhenyu Zhong.

Obesity is a major disease risk factor due to obesity-associated hyperinflammation. We found that obesity induced Nod-like receptor pyrin domain-containing 3 (NLRP3) inflammasome hyperactivation and excessive interleukin (IL)-1β production in macrophages by disrupting SAM and HD domain-containing protein 1 (SAMHD1), a deoxynucleoside triphosphate (dNTP) hydrolase crucial for nucleotide balance. This caused aberrant accumulation of dNTPs, which can be transported into mitochondria, and initiated mitochondrial DNA (mtDNA) neosynthesis, which increased the presence of oxidized mtDNA and triggered NLRP3 hyperactivation. Deletion of SAMHD1 promoted NLRP3 hyperactivation in cells isolated from zebrafish, mice, and humans. SAMHD1-deficient mice showed elevated circulating IL-1β, insulin resistance, and metabolic dysfunction-associated steatohepatitis. Blocking dNTP mitochondrial transport prevented NLRP3 hyperactivation in macrophages from obese patients and SAMHD1-deficient mice. Our study revealed that obesity by inhibiting SAMHD1 rewired macrophage nucleotide metabolism, thereby triggering NLRP3 inflammasome hyperactivation to drive disease progression.

DOI: https://doi.org/10.1126/science.adq9006
bioRxiv. 2026 Jan 06. pii: 2026.01.05.696859. [Epub ahead of print]

Cellular consequences, citrullination substrates, and antigenicity resulting from wild-type and targeted PAD4 on cell surfaces.

Sophie Kong, Trenton M Peters-Clarke, Corleone S Delaveris, Paul Phojanakong, Veronica Steri, James A Wells.

Protein arginine deiminase-4 (PAD4) catalyzes hydrolysis of arginine to citrulline in proteins that promotes widespread changes in cellular phenotypes through transcriptional regulation that can induce innate immunity and promote cancer. Overexpression and hyperactivity of PAD4 leads to a form of cell death called NETosis that releases PAD4 to the extracellular space. In excess, release of PAD4 is believed to be a major cause of various autoimmune diseases through the generation of anti-citrulline protein antibodies (ACPAs). Little is known about the specific protein substrates that become citrullinated and lead to autoimmunity, but there is growing evidence that PAD4 can be localized to the cell surface in response to inflammation. Here, we further characterize the cellular consequences for exogenous treatment with PAD4 showing that it induces morphological changes that increase cell migration, a hallmark of cancer. We then devised a more simplified and robust proteomics approach to identify PAD4 substrates. We identified some 1000 endogenously citrullinated peptides from 500 proteins, and 3000 citrullinated peptides from 1300 proteins upon exogenous addition of PAD4 both inside and outside of cells. This extracellular set can be further augmented by targeting PAD4 to a cancer target, HER2, using a binding protein conjugate. Finally, we studied how citrullinated cells can induce a robust humoral response in a syngeneic vaccine model to produce ACPAs. We believe these studies further our understanding of cell phenotypic consequences of extracellular PAD4 and new PAD4 substrates both inside and outside of cells that are potential neoepitopes for generation of ACPAs.

DOI: https://doi.org/10.64898/2026.01.05.696859
Cell Rep. 2026 Jan 10. pii: S2211-1247(25)01580-3. [Epub ahead of print]45(1): 116808

METTL3-mediated m6A on nascent RNA coordinates translational and transcriptional programs to activate the NLRP3 inflammasome in macrophages.

Jie Fu, Xin Zong, Hong Zhang, Luoyi Zhu, Tao Gong, Yuanzhi Cheng, Fengqin Wang, Zeqing Lu, Caiqiao Zhang, Mingliang Jin, Yizhen Wang.

  NLRP3 inflammasome activation requires both transcriptional priming and complex assembly, but how RNA m6A methylation coordinates these steps remains unclear. Here, we show that m6A levels increase during macrophage NLRP3 inflammasome activation and that METTL3 loss suppresses this activation. Myeloid-specific Mettl3 knockout mice display reduced inflammation and improved metabolic outcomes in lipopolysaccharide (LPS)-induced sepsis, monosodium urate (MSU)-induced arthritis, and diet-induced obesity. Integrated chromatin-associated RNA sequencing (chrRNA-seq), kethoxal-assisted single-stranded DNA sequencing (KAS-seq), and chrRNA-methylated RNA immunoprecipitation (MeRIP)-seq analyses show that METTL3 installs m6A co-transcriptionally on nascent Jak1, Nlrp3, and Il1β RNAs and that METTL3 regulates dynamic transcription and chromatin accessibility while selectively maintaining Nlrp3/Il1β transcription. YTHDF1-driven translation of Jak1 activates the JAK1-STAT3-C/EBPβ axis to initiate Nlrp3/Il1β transcription, and m6A-YTHDF1 translation of Nlrp3/Il1β amplifies protein output, forming a coupled transcriptional-translational circuit. Pharmacologic STAT3 inhibition and METTL3 catalytic rescue validate this pathway and identify METTL3-mediated m6A as a therapeutic target for inflammasome-driven diseases.

Keywords:  CP: Immunology; CP: Molecular biology; METTL3; NLRP3 inflammasome; m(6)A methylation; macrophage; transcription; translation

DOI:  https://doi.org/10.1016/j.celrep.2025.116808