bims-cediti Biomed News
on Cell death in innate immunity, inflammation, and tissue repair
Issue of 2025–11–02
twelve papers selected by
Kateryna Shkarina, Universität Bonn
  1. Activation and regulation of NAIP/NLRC4 and NLRP3 inflammasomes during Salmonella infection: mechanisms and therapeutic implications.
  2. SARM1 senses dsDNA to promote NAD+ degradation and cell death.
  3. Pharmacological targeting of RIG-I can selectively activate the integrated stress response.
  4. Cytosolic TOP3α facilitates mitochondrial DNA sensing by cGAS.
  5. A gasdermin-based life-death evolution system for reprogramming protease specificity.
  6. Autonomous STING signaling in Purkinje cells drives neurodegeneration independent of type I interferon.
  7. Structural basis of apoptosis induction by the mitochondrial voltage-dependent anion channel.
  8. Structural basis for amyloid fibril assembly by the master cell-signaling regulator receptor-interacting protein kinase 1.
  9. A cell-based scrambling assay reveals the phospholipid headgroup preference of TMEM16F on the plasma membrane.
  10. Selective and Orally Bioavailable Dipeptidyl Peptidase 9 Inhibitors with Potent Pyroptosis Induction Properties.
  11. FerrDb V3: expanding the manually curated resource for regulators and disease associations from ferroptosis to regulated cell death.
  12. FSP1-mediated lipid droplet quality control prevents neutral lipid peroxidation and ferroptosis.
  1. Mol Biol Rep. 2025 Oct 29. 53(1): 21
    Activation and regulation of NAIP/NLRC4 and NLRP3 inflammasomes during Salmonella infection: mechanisms and therapeutic implications.
    Yeling He, Dandan Ding, Jiayin Guo, Hui Sun, Jing Yang.
      Inflammasomes constitute a critical component of host defense against Salmonella infection, among which the NAIP/NLRC4 and NLRP3 complexes serve as the two principal signaling platforms. The NAIP/NLRC4 inflammasome functions as a rapid-response sensor that specifically recognizes bacterial flagellin and T3SS components, leading to caspase-1 activation, GSDMD-mediated pyroptosis, and IL-1β/IL-18 maturation. In contrast, NLRP3 integrates broad cellular stress signals, such as K⁺ efflux, mitochondrial ROS, and lysosomal damage, to amplify and sustain inflammatory responses, particularly at later stages of infection. This review synthesizes the current understanding of the structural basis, activation mechanisms, and spatiotemporal dynamics of these inflammasomes across immune and epithelial compartments. We further outline multilayered regulatory networks, including nuclear receptors, epigenetic regulators, post-translational modifications, non-coding RNAs, and autophagy-lysosome factors, that fine-tune inflammasome activity. Species-specific differences are emphasized, particularly the role of caspase-4/5 in human non-canonical signaling versus caspase-11 in mice. The functional interplay between NAIP/NLRC4 and NLRP3 is also examined, covering redundancy, cooperation, and potential antagonism. Finally, we discuss translational opportunities for targeting inflammasomes, including probiotics, postbiotics, and natural compounds, as antibiotic-sparing strategies in the context of antimicrobial resistance. Collectively, these insights delineate a multilayered host defense system and identify promising targets for immunomodulatory interventions against Salmonella.
    Keywords:   Salmonella enterica ; Caspase; Inflammasome; Inflammasome-targeted immunotherapy; NAIP; NLRC4; NLRP3; Pyroptosis; Type III secretion system (T3SS)
    DOI:  https://doi.org/10.1007/s11033-025-11166-y
  2. Cell. 2025 Oct 24. pii: S0092-8674(25)01126-2. [Epub ahead of print]
    SARM1 senses dsDNA to promote NAD+ degradation and cell death.
    Lina Wang, Qiaoling Liu, Siru Li, Na Wang, Yan Chen, Junren Chen, Li Wang, Yuelin Huang, Zhen Sun, Ling Dong, Shao Li, Quentin Liu, Song Gao, Xiaochi Ma, Chengli Song, Qingkai Yang.
      Detection of DNA is a fundamental strategy for life to recognize non-self or abnormal-self to subsequently trigger the downstream responses. However, the mechanism underlying DNA sensing is incompletely understood. Here, we show that a key neural executioner, sterile alpha and Toll/interleukin-1 receptor (TIR) motif containing 1 (SARM1), senses double-stranded DNA (dsDNA) to promote cell death. dsDNA-bound and -activated SARM1 to degrade nicotinamide adenine dinucleotide (NAD+) in a sequence-independent manner. SARM1 bound dsDNA via the TIR domain, and lysine residues in the TIR domain contributed to dsDNA binding. In the cellular context, cytosolic dsDNA from dsDNA transfection or chemotherapy treatment was colocalized with SARM1 and activated SARM1 to elicit NAD+ degradation and cell death, which was abrogated by SARM1 knockout or DNA-binding residue mutation. Consistently, SARM1 knockout blocked chemotherapy-induced neuropathy (CIN) in mice. Our results reveal SARM1 as a DNA sensor, which might be targetable for therapeutic interventions.
    Keywords:  CIN; DNA sensor; NAD; SARM1; TIR domain; axon degeneration; cancer; cell death; chemotherapy-induced neuropathy; metabolism
    DOI:  https://doi.org/10.1016/j.cell.2025.09.026
  3. Sci Adv. 2025 Oct 31. 11(44): eadt3014
    Pharmacological targeting of RIG-I can selectively activate the integrated stress response.
    Caroline A Cuoco, Wen Ren, Kelsey R Baron, Sakina Gologo, Valerie Perea, Prakhyat Mathur, Prerona Bora, Amina Ta, Alan Chu, Rama Aldakhlallah, Derek Rhoades, Christian M Cole, Ee Phie Tan, William C Hou, Leonard Yoon, Xiaoyan Guo, Jessica D Rosarda, Phil S Baran, Martin Kampmann, Lakeisha Tillery, Kristen A Johnson, Evan T Powers, R Luke Wiseman, Jeffery W Kelly.
      The integrated stress response (ISR) is a eukaryotic stress-responsive signaling pathway that attenuates global protein synthesis while allowing selective translation of specific mRNAs, which together can reestablish homeostasis following acute stress. Diverse pathologic insults activate one or more of the four ISR kinases, which selectively phosphorylate eIF2α to mediate ISR functions. Recent results suggest that enhancing ISR kinase activity could ameliorate pathologies linked to numerous diseases, including many neurodegenerative disorders. However, few pharmacological strategies exist to selectively activate ISR kinases and downstream adaptive signaling. Here, we report that compound A8 can preferentially activate the ISR through the binding of the cytosolic pattern recognition receptor RIG-I, which subsequently activates the heme-regulated inhibitor (HRI) ISR kinase independent of an interferon response. The establishment of A8 and its active metabolite CC81 provides opportunities to probe the biological and therapeutic relationship between innate immune signaling and ISR activation in health and disease.
    DOI:  https://doi.org/10.1126/sciadv.adt3014
  4. EMBO Rep. 2025 Oct 30.
    Cytosolic TOP3α facilitates mitochondrial DNA sensing by cGAS.
    Dongjing Cai, Cheng Chen, Piyanat Meekrathok, Weiqian Zeng, Zheng Wang, Zhigang Peng, Yunan Mo, Xia Xu, Junling Wang, Jian Qiu.
      Mitochondrial DNA (mtDNA) serves as a potent activator for cellular innate immune responses. Topoisomerase 3α (TOP3α), a type IA topoisomerase, is canonically localized to mitochondria and nuclei, but its enigmatic cytosolic fraction-observed over two decades ago-has remained functionally undefined. Here, we uncover a critical role for cytosolic TOP3α in amplifying mtDNA-triggered innate immunity. We observe that aberrant TOP3α expression causes mtDNA clustering and release via mPTP-VDAC, stimulating cGAS-mediated inflammatory responses. Cytosolic TOP3α facilitates the sensing of released mtDNA by cGAS and amplifies downstream innate immune signaling. Using an in vitro cell-free system, we reveal that TOP3α directly augments mtDNA interaction with cGAS, which in turn competes with TOP3α for mtDNA binding. A rare mutation of a highly conserved residue (G250D) of TOP3α impairs the assembly of TOP3α polypeptides into protein complexes and its binding to mtDNA. Furthermore, mutant TOP3α hinders cGAS-mtDNA interaction and compromises cGAS-driven immunity. Our findings reveal a function for cytosolic TOP3α as a regulator for cGAS-driven inflammation.
    Keywords:  Cytosolic TOP3α; Inflammation; Mitochondrial DNA; cGAS
    DOI:  https://doi.org/10.1038/s44319-025-00614-2
  5. Nat Chem Biol. 2025 Oct 31.
    A gasdermin-based life-death evolution system for reprogramming protease specificity.
    Ziqi Gao, Tianzhen Li, Hao Ye, William Shu Ching Ngai, Huijie Wang, Peng R Chen, Jie Wang.
      Reprogramming the specificity of proteases toward alternative target sequences could enable an array of exciting applications, ranging from proteome editing to therapeutic interventions. Here we report an in vivo life-death selection system for protease reprogramming using the toxic N-terminal domain of gasdermin D (GD-N) protein as a selection marker. The approach is a modular system that can be used to cover the protease mutational diversity in the billions through only a few cycles of directed evolution. By inserting the desired cleavage sequence into the loop region of the GD-N protein, which is toxic to host bacteria cells, the system selects for efficient substrate cleavage-rendering GD-N nontoxic-by enrichment of bacteria in liquid culture. Using the tobacco etch virus protease (TEVp) and corresponding substrate sequence as a model, we demonstrated that our platform could select and enrich an efficient protease variant millionfold after a single round of selection. We also evolve TEVp to cut sequences on target proteins with known pathological roles.
    DOI:  https://doi.org/10.1038/s41589-025-02063-3
  6. Cell Rep. 2025 Oct 29. pii: S2211-1247(25)01251-3. [Epub ahead of print]44(11): 116480
    Autonomous STING signaling in Purkinje cells drives neurodegeneration independent of type I interferon.
    Kun Yang, Miranda Dunn, Gustavo Torres-Ramirez, Nicole Dobbs, Vikram G Shakkottai, Nan Yan.
      STING signaling is emerging as a critical component of neurodegenerative diseases. While microglial STING-type I interferon (IFN-I) signaling is well-established, the role of STING signaling in neurons remains unclear. Here, we show that the STING protein is expressed in Purkinje cells of the cerebellum. Selective activation of STING signaling only in Purkinje cells using a conditional constitutively active N153S allele results in progressive neuronal loss and cerebellar atrophy, astrogliosis, but no microgliosis, leading to severe motor impairments in mice. Surprisingly, Purkinje cell STING activation does not induce IFN-I response. IFN-I receptor (Ifnar1) knockout also does not mitigate Purkinje cell STING-mediated neurodegeneration. Electrophysiological analyses reveal that Purkinje cell STING signaling reduces autonomous firing, which is essential for pace-making and neuronal function. Together, these findings demonstrate the physiological significance of IFN-independent STING function in Purkinje neurons and highlight its divergence from microglial STING signaling.
    Keywords:  CP: Cell biology; CP: Neuroscience; IFN; Purkinje cells; STING; neurodegeneration; neuroinflammation
    DOI:  https://doi.org/10.1016/j.celrep.2025.116480
  7. Nat Commun. 2025 Oct 27. 16(1): 9481
    Structural basis of apoptosis induction by the mitochondrial voltage-dependent anion channel.
    Melina Daniilidis, Umut Günsel, Georgios Broutzakis, Kira D Leitl, Robert Janowski, Kai Fredriksson, Dierk Niessing, Christos Gatsogiannis, Franz Hagn.
      The voltage-dependent anion channel (VDAC) is the main gateway for metabolites across the mitochondrial outer membrane. VDAC oligomers are connected to apoptosis induced by various stimuli. However, the mechanistic and structural basis of apoptosis induction by VDAC remains poorly understood. Here, using cryo-EM and NMR we show that VDAC1 oligomerization or confinement in small lipid nanodiscs triggers the exposure of its N-terminal α-helix (VDAC1-N) which becomes available for partner protein binding. NMR and X-ray crystallography data show that VDAC1-N forms a complex with the BH3 binding groove of the anti-apoptotic Bcl2 protein BclxL. Biochemical assays demonstrate that VDAC1-N exhibits a pro-apoptotic function by promoting pore formation of the executor Bcl2 protein Bak via neutralization of BclxL. This mechanism is reminiscent of BH3-only sensitizer Bcl2 proteins that are efficient inducers of Bax/Bak-mediated mitochondrial outer membrane permeabilization and ultimately apoptosis. The VDAC pathway most likely responds to mitochondrial stress or damage.
    DOI:  https://doi.org/10.1038/s41467-025-65363-1
  8. Nat Commun. 2025 Oct 30. 16(1): 9607
    Structural basis for amyloid fibril assembly by the master cell-signaling regulator receptor-interacting protein kinase 1.
    Paula Polonio, Jorge Pedro López-Alonso, Hanxing Jiang, Sara Andrés-Campos, Fátima C Escobedo-González, Gustavo A Titaux-Delgado, Iban Ubarretxena-Belandia, Miguel Mompeán.
      Amyloid fibrils can form biologically relevant functional assemblies. The RIP homotypic interaction motifs (RHIMs) in receptor-interacting protein kinases 1 and 3 (RIPK1 and RIPK3) orchestrate the formation of amyloid-like fibrils essential for propagating cell death signals. While the structures of human RIPK3 (hRIPK3) homomeric fibrils and RIPK1-RIPK3 heteromeric fibrils have been elucidated, the atomic structure of human RIPK1 (hRIPK1) homomeric fibrils has remained elusive. We present a high-resolution structure of hRIPK1 RHIM-mediated amyloid fibrils, determined using an integrative approach combining cryoprobe-detected solid-state nuclear magnetic resonance spectroscopy and cryo-electron microscopy. The fibrils adopt an N-shaped fold consisting of three β-sheets stabilized by hydrophobic interactions and hydrogen bonding. A key hydrogen bond between N545 and G542 closes the β2-β3 loop, resulting in denser side-chain packing compared to hRIPK3 homomeric fibrils. These findings provide structural insights into how hRIPK1 homomeric fibrils nucleate hRIPK3 recruitment and fibrillization during necroptosis, offering broader perspectives on the molecular principles governing RHIM-mediated amyloid assembly and functional amyloids.
    DOI:  https://doi.org/10.1038/s41467-025-64621-6
  9. Proc Natl Acad Sci U S A. 2025 Nov 04. 122(44): e2516822122
    A cell-based scrambling assay reveals the phospholipid headgroup preference of TMEM16F on the plasma membrane.
    Chin Fen Teo, Sami T Tuomivaara, Niek van Hilten, David Crottès, Yuh Nung Jan, Michael Grabe, Lily Y Jan.
      The asymmetric resting distribution of the three major phospholipid classes on the mammalian plasma membrane, with phosphatidylserine and phosphatidylethanolamine mostly on the inner leaflet and phosphatidylcholine mostly on the outer leaflet, is maintained by ATP-dependent flippases and floppases that exhibit headgroup selectivity. Upon signaling cues, this asymmetry can be dissipated by various phospholipid scramblases, allowing cells to respond to stimuli and adapt to different physiological contexts. The prevailing view in the field is that phospholipid scramblases on the plasma membrane act without headgroup preference. Here, we report contrary experimental evidence based on a phospholipid scrambling assay that quantifies the fluorescence polarization (FP) of nitrobenzoxadiazole (NBD)-labeled phospholipids for kinetic monitoring of phospholipid scrambling on the plasma membrane of living cells. Our experiments reveal that the plasma membrane-residing calcium-activated phospholipid scramblase TMEM16F preferentially acts on phosphatidylserine and phosphatidylcholine over phosphatidylethanolamine.
    Keywords:  TMEM16F; coarse-grained molecular simulations; fluorescence polarization; phospholipid scrambling; plasma membrane
    DOI:  https://doi.org/10.1073/pnas.2516822122
  10. J Med Chem. 2025 Oct 29.
    Selective and Orally Bioavailable Dipeptidyl Peptidase 9 Inhibitors with Potent Pyroptosis Induction Properties.
    Nicolò Filippi, Kathleen Mertens, Joni De Loose, Siham Benramdane, Robin Hermans, Margarida Espadinha, Laura Dirkx, Pim-Bart Feijens, Vanesa Nozal, Emile Verhulst, Sarah Peeters, Tiphanie Gomard, Sam Corthaut, Koen Augustyns, Guy Caljon, Dominique Schols, Ingrid De Meester, Pieter Van der Veken.
      Dipeptidyl peptidase 9 (DPP9) is a key regulator of pyroptosis in leukocytes. DPP9-targeting inhibitors have been reported to selectively induce pyroptosis in human acute myeloid leukemia (AML) cells and work synergistically with non-nucleoside reverse transcriptase inhibitors (NNRTIs) to kill HIV-1-infected lymphocytes. Here, we report structure-activity relationship data for a novel series of low nanomolar DPP9 inhibitors with unprecedented pyroptosis-inducing potency and kinetics. They have substantial DPP9-to-DPP8 selectivity and full selectivity over other related peptidases, including DPP4. The selected compound 6e was administered to healthy rats and demonstrated high oral bioavailability, along with a long in vivo and microsomal half-life. Finally, we also investigated the pyroptosis induction potential in HIV-1-infected T-lymphocytes. These new compounds have the potential to become important research tools and support further progress in DPP9's therapeutic potential.
    DOI:  https://doi.org/10.1021/acs.jmedchem.5c02049
  11. Nucleic Acids Res. 2025 Oct 31. pii: gkaf1119. [Epub ahead of print]
    FerrDb V3: expanding the manually curated resource for regulators and disease associations from ferroptosis to regulated cell death.
    Nan Zhou, Li Peng, Qiqi Luo, Tong Yin, Huiran Sun, Yuhong Zhang, Xiaolei Shi, Xian Peng, Jinku Bao, Yuping Ning, Xiaoqing Yuan.
      Regulated cell death (RCD) is essential to both physiological homeostasis and numerous diseases. FerrDb is a curated database for ferroptosis regulators and ferroptosis-disease associations. Though widely used, FerrDb is limited by its singular focus on ferroptosis. The field of cell death is rapidly expanding, marked by continuous discovery of novel RCD modalities. The need for a high-quality database that encompasses the entire spectrum of RCD is urgent, but none exists. Here, we introduce FerrDb V3, an upgraded version featuring extensive enhancements in content and functionality. Remarkably, it expands from the focus on ferroptosis to 22 RCD modalities. RCD regulators and RCD-disease associations were manually curated from >20 000 articles. Database content was additionally enriched by public resources. A conversational intelligent assistant that enables users to explore the database through natural language queries was created. A suite of web-based analytical utilities tailored for RCD research was developed. The web interface was updated accordingly to offer a seamless user experience. In conclusion, FerrDb V3 has evolved into a comprehensive resource and a valuable research tool for the RCD research community. FerrDb V3 is freely accessible at https://www.zhounan.org/ferrdb/.
    DOI:  https://doi.org/10.1093/nar/gkaf1119
  12. Nat Cell Biol. 2025 Oct 29.
    FSP1-mediated lipid droplet quality control prevents neutral lipid peroxidation and ferroptosis.
    Mike Lange, Michele Wölk, Vivian Wen Li, Cody E Doubravsky, Joseph M Hendricks, Shunji Kato, Yurika Otoki, Benjamin Styler, Sean L Johnson, Cynthia A Harris, Kiyotaka Nakagawa, Isabel F Snodgrass, Dohee Kim, John W Newman, Maria Fedorova, James A Olzmann.
      Lipid droplets (LDs) are organelles that store and supply lipids, based on cellular needs. Although mechanisms preventing oxidative damage to membrane phospholipids are established, the vulnerability of LD neutral lipids to peroxidation and protective mechanisms are unknown. Here we identify LD-localized ferroptosis suppressor protein 1 (FSP1) as a critical regulator that prevents neutral lipid peroxidation by recycling coenzyme Q10 (CoQ10) to its lipophilic antioxidant form. Lipidomics reveal that FSP1 loss leads to the accumulation of oxidized triacylglycerols and cholesteryl esters, and biochemical reconstitution of FSP1 with CoQ10 and NADH suppresses triacylglycerol peroxidation in vitro. Notably, inducing polyunsaturated fatty acid-rich LDs triggers triacylglycerol peroxidation and LD-initiated ferroptosis when FSP1 activity is impaired. These findings uncover the first LD lipid quality-control pathway, wherein LD-localized FSP1 maintains neutral lipid integrity to prevent the build-up of oxidized lipids and induction of ferroptosis.
    DOI:  https://doi.org/10.1038/s41556-025-01790-y
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