bims-cediti 2025-09-28 papers

bims-cediti

Biomed News

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

Issue of 2025–09–28
twelve papers selected by
Kateryna Shkarina, Universität Bonn

RIPK1 autophosphorylation at S161 mediates cell death and inflammation.
For Better or Worse: The Impact of Necrotic Cell Death Modalities.
Targeting the NLRP3 Inflammasome-Gasdermin D Axis to Combat Cardiovascular Diseases.
Evolving methodologies for identification and differentiation of regulated cell death modalities.
The viral BCL2 protein BHRF1 of Epstein-Barr virus promotes AIM2 inflammasome activation to facilitate lytic replication.
USP13 stabilizes NLRP3 to facilitate inflammasome activation by preventing TRIM31-mediated NLRP3 ubiquitination and degradation.
Taurine transport is a critical modulator of ionic fluxes during NLRP3 inflammasome activation.
RIPK1 S161 phosphorylation promotes further autophosphorylation and cecal necroptosis in TNF-treated mice.
Visualizing and mapping cell death: Biochemical tools, techniques and assays.
Cell Death and Infection: Implications for Host and Microbe.
Entosis in Health and Disease.
Live-cell imaging with fluorogenic radical-trapping antioxidant probes reveals the onset and progression of ferroptosis.

J Exp Med. 2025 Dec 01. pii: e20250279. [Epub ahead of print]222(12):

RIPK1 autophosphorylation at S161 mediates cell death and inflammation.

Lioba Koerner, Xiaoming Li, Eveline Silnov, Lucie Laurien, Manolis Pasparakis.

RIPK1 regulates cell death and inflammation and has been implicated in the pathogenesis of inflammatory diseases. RIPK1 autophosphorylation promotes cell death induction; however, the underlying mechanisms and the role of specific autophosphorylation sites remain elusive. Using knock-in mouse models, here we show that S161 autophosphorylation has a critical physiological function in RIPK1-mediated cell death and inflammation. S161N substitution partially suppressed RIPK1-mediated catalytic activity and cell death induction but was sufficient to prevent skin inflammation induced by keratinocyte necroptosis or apoptosis in relevant mouse models. Combined S161N and S166A mutations synergized to prevent RIPK1-mediated cell death more efficiently than the single site mutations, revealing functional redundancy. Moreover, phosphomimetic S161E mutation could overcome the necroptosis-inhibitory effect of S166A mutation, revealing that S161 phosphorylation is sufficient for necroptosis induction. Collectively, a functional interplay of S161 and S166 phosphorylation events regulates RIPK1-dependent cell death and inflammation.

DOI: https://doi.org/10.1084/jem.20250279
Adv Exp Med Biol. 2025 ;1481 241-292

For Better or Worse: The Impact of Necrotic Cell Death Modalities.

Peter Vandenabeele, Marcus Conrad, Adam Wahida.

  Cellular stress, infection, and inflammation lead to various forms of cell death. Depending on the stimulus, cell type, and cellular conditions, different modes of regulated cell death might be engaged. These include apoptosis, necroptosis, and pyroptosis, which are driven by genetically programmed mechanisms, and ferroptosis, a type of metabolic cell death. The outcome of these distinct cell death modalities is the activation of specific pore-forming mechanisms: caspase-3-mediated cleavage of gasdermin E in secondary necrosis following apoptosis (also classified as pyroptosis), RIPK3-mediated phosphorylation of MLKL in necroptosis, and caspase-1/11/4/5-mediated cleavage of GSDMD during pyroptosis. In the case of ferroptosis, a metabolic cell death modality driven by imbalances in iron, lipid, and redox metabolism, the plasma membrane also becomes permeabilized due to oxidative modifications of acyl chains in phospholipids. On top of the pore-forming mechanisms, NINJ1 detects cellular swelling ("oncosis") and triggers a massive plasma membrane rupture as a final stage of the cellular cataclysm, releasing large molecules and intracellular contents. Understanding the mechanisms of regulated necrotic cell death through signaling pathways or by disrupting metabolic networks offers tangible targeting strategies to enhance or reduce cell death processes and associated subroutines in various diseases, including cancer, ischemia/reperfusion conditions, inflammation, and degenerative diseases. Besides the molecular biology, we will concentrate this chapter on the effects of necroptosis, pyroptosis, and ferroptosis in cancer and inflammatory pathologies in the brain, intestine, and skin.

Keywords:  Ferroptosis; GSDM; MLKL; Metabolic cell death; NINJ1; Necroptosis; Necrotic cell death in cancer; Necrotic cell death in pathological immunity; Pyroptosis; Regulated necrotic cell death

DOI:  https://doi.org/10.1007/978-3-031-92785-0_8
J Mol Cell Cardiol. 2025 Sep 23. pii: S0022-2828(25)00175-0. [Epub ahead of print]

Targeting the NLRP3 Inflammasome-Gasdermin D Axis to Combat Cardiovascular Diseases.

Judy S Choi, Mehnaz Pervin, James E Vince, Arpeeta Sharma, Judy B de Haan.

  Cardiovascular disease remains a leading global cause of mortality, with inflammation playing a crucial role in driving its pathology. Despite advancements in cardiovascular disease management, current treatment options primarily address risk factors and symptoms rather than underlying disease mechanisms. Among the key mechanistic drivers are the NLRP3 multiprotein inflammasome complexes of the innate immune system, which are activated in response to cellular stress or injury. One of the key downstream effectors of NLRP3 activation is gasdermin D, which forms pores in the plasma membrane to initiate pyroptotic cell death, leading to the release of pro-inflammatory cytokines. This review will highlight the role of NLRP3 inflammasome activation and gasdermin D-mediated pyroptosis in driving cardiovascular diseases, including atherosclerosis, myocardial infarction, ischemic stroke and diabetic cardiomyopathy. It will also identify recent innovative therapeutic approaches that target the NLRP3 inflammasome-gasdermin D axis, which are currently being evaluated in preclinical studies and clinical trials.

Keywords:  Cardiovascular disease; NLRP3 inflammasome; gasdermin D; inflammation; pyroptosis

DOI:  https://doi.org/10.1016/j.yjmcc.2025.09.006
Prog Mol Biol Transl Sci. 2025 ;pii: S1877-1173(25)00110-3. [Epub ahead of print]217 25-65

Evolving methodologies for identification and differentiation of regulated cell death modalities.

Anmol Kaur, Urvi, Rajeev Kumar Pandey, Sanjana Mehrotra.

  Cell death is a crucial evolutionary adaptation for multicellular organisms through which they can systematically eliminate cells that are no longer needed, potentially harmful, or are damaged beyond repair. Over the past few decades, our understanding of the cell death mechanisms has expanded significantly revealing a diverse, and interconnected array of regulated cell death (RCD) pathways that includes apoptosis, necroptosis, pyroptosis, cuproptosis etc. While the complexities of these pathways have incrementally increased with the evolution of multicellularity, many core components associated with cell death have remained conserved. This points towards the essential function of cell death in maintenance of homeostasis at the cellular, organismal and individual level. It is thus not a surprise that their dysregulation can manifest in the form of several pathologies. Therefore, the ability to accurately detect and distinguish different forms of cell death is essential not only for advancing our understanding of the fundamental cellular and molecular processes but also for elucidating their role in disease pathogenesis, where their dysregulation contributes to various pathological conditions. However, detecting and differentiating various forms of cell death is a challenging task. Since there are multiple cell death modalities, many of their characteristics overlap, such as a condensed nucleus being observed in both secondary necrosis and apoptosis. Further, a cell can undergo more than one kind of cell death simultaneously, a process known as "cell death continuum" further complicating detection and classification. This chapter provides an overview of the conventional methods used for detecting cell death, highlighting both probe-based and non-probe-based techniques. Recent advancements in high-throughput strategies, AI based predictive modelling and other such novel techniques that offer greater specificity in cell death characterization are particularly emphasized.

Keywords:  Apoptosis; Autophagy; Biosensors; Cell death detection; Cuproptosis; Ferroptosis; Live-cell imaging; Microscopy; Necroptosis

DOI:  https://doi.org/10.1016/bs.pmbts.2025.06.023
PLoS Pathog. 2025 Sep 22. 21(9): e1013509

The viral BCL2 protein BHRF1 of Epstein-Barr virus promotes AIM2 inflammasome activation to facilitate lytic replication.

Qingping Lan, Xiaolin Zhang, Yifan Sun, Jing Yang, Xiaojuan Li, Ersheng Kuang.

The absent in melanoma 2 (AIM2) protein recognizes viral and naked dsDNA and recruit apoptosis-associated speck-like protein containing CARD (ASC) to initiate inflammasome activation; however, the subversion of AIM2 activation by Epstein-Barr virus (EBV) infection remains unknown. Here, we reveal that the EBV-encoded viral BCL2 protein BHRF1 promotes AIM2 inflammasome activation. The BHRF1 C-terminal domain binds to AIM2 HIN domain and directly promotes dsDNA recognition and AIM2-ASC interaction, consequently cooperates with viral dsDNA to enable inflammasome activation. The single-site mutations R162A and F164A in BHRF1 and E186A in AIM2 abolish their interaction and AIM2 inflammasome activation. BHRF1 recruits AIM2 inflammasome to the mitochondrial compartment and facilitates EBV lytic replication through KAP1 and GSDMD cleavage. BHRF1 deficiency strongly decreases AIM2 inflammasome activation and EBV lytic replication, and reintroduction of wild-type BHRF1 but not the BHRF1 R162A or F164A mutant restores these functions. These results suggest that BHRF1 protein directly promotes the AIM2 inflammasome activation in the mitochondrial compartment to facilitate lytic replication.

DOI: https://doi.org/10.1371/journal.ppat.1013509
Sci Adv. 2025 Sep 26. 11(39): eadx3827

USP13 stabilizes NLRP3 to facilitate inflammasome activation by preventing TRIM31-mediated NLRP3 ubiquitination and degradation.

Ya-Ting Li, Ke-Ying Li, Shou-Song Tao, Ting Wang, Ying Lu, Hui Chen, Yi-Qun Zhan, Ke Zhao, Shen-Si Xiang, Jing-Jing Li, Hui-Ying Gao, Miao Yu, Chang-Yan Li, Lin Wang, Xiao-Ming Yang, Guang-Ming Ren, Rong-Hua Yin.

NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) has a fundamental role in host defense and is involved in diverse inflammatory diseases. NLRP3 protein expression is tightly controlled by the ubiquitin system. In particular, NLRP3 protein degradation has been extensively studied. In contrast, the mechanisms to stabilize NLRP3 protein are much less known. Here, we demonstrated the critical role of ubiquitin-specific protease 13 (USP13) in regulating NLRP3 protein stability and inflammasome activation independently of its deubiquitinating enzyme activity. USP13 competes with E3 ubiquitin ligase TRIM31 to interact with NLRP3 and prevents TRIM31-mediated NLRP3 ubiquitination at K192 and K496 sites, thereby inhibiting proteasomal degradation of NLRP3. USP13 deficiency reduces NLRP3 protein expression in both human and mouse macrophages, which consequently inhibits NLRP3 inflammasome assembly and activation. Accordingly, deficiency of USP13 attenuates monosodium urate crystal-induced mouse peritonitis. Overall, our findings reveal a previously unrecognized regulatory mechanism of NLRP3 stability by USP13 and provide a potential therapeutic target for NLRP3-driven diseases.

DOI: https://doi.org/10.1126/sciadv.adx3827
Cell Rep. 2025 Sep 18. pii: S2211-1247(25)01088-5. [Epub ahead of print]44(10): 116317

Taurine transport is a critical modulator of ionic fluxes during NLRP3 inflammasome activation.

Peter Rossi-Smith, Joohee Kim, Kamil Skirlo, Trevor Ferris, Jack P Green, Cari Stek, Kristin K Huse, Paige M Mortimer, Antoni Olona, Cecilia Wieder, Raymond Moseki, Mariana Silva Dos Santos, James I MacRae, Shiranee Sriskandan, Timothy M D Ebbels, Robert J Wilkinson, Alice E Denton, Nicolas J Matheson, Paras K Anand, Graeme Meintjes, David C Thomas, Rachel P J Lai.

  Metabolic regulation is a key feature of inflammasome activation and effector function. Using metabolomic approaches, we show that downregulation of taurine metabolism is crucial for NLRP3 inflammasome activation. Following NLRP3 activation stimuli, taurine rapidly egresses to the extracellular compartment. Taurine efflux is facilitated primarily by the volume-regulated anion channel (VRAC). Loss of intracellular taurine impairs sodium-potassium ATPase pump activity, promoting ionic dysregulation and disrupting ionic fluxes. Inhibiting VRAC, or supplementation of taurine, restores the ionic balance, abrogates IL-1β release, and reduces cellular cytotoxicity in macrophages. We further demonstrate that the protective effect of taurine is diminished when sodium-potassium ATPase is inhibited, highlighting the pump's role in taurine-mediated protection. Finally, taurine metabolism is significantly associated with the development of tuberculosis-associated immune reconstitution inflammatory syndrome, a systemic hyperinflammatory condition known to be mediated by inflammasome activation. Altogether, we identified a critical metabolic pathway that modulates inflammasome activation and drives disease pathogenesis.

Keywords:  ATPase; CP: Metabolism; inflammasome; inflammation; ion channels; ionic fluxes; metabolism; metabolomics; taurine; tuberculosis

DOI:  https://doi.org/10.1016/j.celrep.2025.116317
J Exp Med. 2025 Dec 01. pii: e20250277. [Epub ahead of print]222(12):

RIPK1 S161 phosphorylation promotes further autophosphorylation and cecal necroptosis in TNF-treated mice.

Tao Han, Chenchen Ruan, Huiyong Lin, Yuxia Zhang, Lang Li, Ye-Hsuan Sun, Chuan-Qi Zhong, Xin Chen, Kai Huang, Yating Cao, Zusen Fan, Hongbing Zhang, Jiahuai Han, Yingying Zhang.

Excess TNF causes systemic inflammatory response syndrome and mortality. RIPK1 coordinates TNF signaling through kinase-dependent and -independent mechanisms. S161 autophosphorylation is a primary function of RIPK1 kinase activity in vitro, and here we show that it is sufficient to mediate RIPK1 kinase-dependent function in vivo. S161 phospho-mimic mutation (S161E) effectively overcomes chemical or genetic inhibition of RIPK1 kinase activity in TNF-treated cells and mice. Mechanistically, S161 autophosphorylation is necessary for further autophosphorylation in RIPK1, including at S166. Ripk1S161E/S161E mice are hypersensitive to TNF, enabling us to observe low-dose TNF-induced necroptosis in cecal intestinal epithelial cells (IECs) and endothelial cells (ECs) and uncover a reciprocal enhancement between IEC and EC necroptosis and a selective increase of IL-6 in the circulation by necroptosis. IL-6 promotes cecal edema and synergizes with IEC and EC necroptosis, causing cecal damage and mouse death. Our data elucidate a mechanism of RIPK1 kinase-dependent function in TNF signaling and its role in cecal pathology and mouse mortality.

DOI: https://doi.org/10.1084/jem.20250277
Prog Mol Biol Transl Sci. 2025 ;pii: S1877-1173(25)00105-X. [Epub ahead of print]217 81-107

Visualizing and mapping cell death: Biochemical tools, techniques and assays.

Sadhna Soni, Ashwini Nath Tiwari, Amrendra Singh, Arun Upadhyay.

  Cell death is a fundamental process that plays a role in the development of multicellular organisms, tissue homeostasis, and fighting infections. Dysfunctional cell death signaling is associated with many diseases, including cancer. Most studied among multiple possible cell death pathways is apoptosis that is essential for various biological functions, including embryogenesis, aging, and the development of numerous diseases. This regulated cell death enables the removal of cells in a controlled manner, maintaining tissue homeostasis and aiding organismal development. Understanding cell death pathways can help develop new therapeutic strategies for treating diseases like cancer. For example, tumor cells often avoid apoptosis, which can lead to treatment resistance. Various groups of researchers believe that studying other cell death pathways, like necroptosis, pyroptosis, ferroptosis, and cuproptosis, may have high potential for cancer therapy. Numerous biochemical methods exist to detect, quantify, and analyze cell death pathways, each with unique principles, advantages, and limitations. A comprehensive understanding of these methods enables researchers to select appropriate techniques for their experimental contexts. This chapter systematically discusses the molecular and cellular changes related to various cell death pathways and the conventional and non-conventional methods used to investigate these processes.

Keywords:  Apoptosis; Cancer; Cell cycle; Detection methods; Programmed cell death

DOI:  https://doi.org/10.1016/bs.pmbts.2025.06.018
Adv Exp Med Biol. 2025 ;1481 207-240

Cell Death and Infection: Implications for Host and Microbe.

Anna Davey, Thibaut Sanchez, Christopher D Lucas, Christopher J Anderson.

  Cell death is a part of life. Every day, billions of cells undergo programmed cell death within the human body as part of normal tissue turnover and homeostasis. The factors that initiate programmed cell death, the resulting signalling pathways that occur within the dying cell, the means to dispose of the dying cell, and the response of the neighbouring tissue to the dying cell are all highly evolutionarily conserved and tightly regulated processes. Decades of outstanding research have identified critical components of programmed cell death initiation, corpse clearance, and tissue response, particularly in the context of homeostatic cell death or sterile injury-induced cell death; however, multiple tissues are not sterile under homeostasis. In particular, the intestinal and respiratory tracts are 'external environment-facing' tissues that are in constant contact with commensal microorganisms and are also frequently exposed to invading pathogenic microbes. Indeed, many pathogenic microbes are capable of inducing or inhibiting various forms of cell death during infection, and some go as far as to utilise the metabolites released to the environment during apoptosis for their own growth. The primary emphasis of the field has been on the identification of what form of programmed cell death is initiated during infection and what the immunological consequences are. In contrast, less is known about how the critical stages of cell death and cell clearance directly or indirectly impact the microbes (both commensal and pathogenic) themselves. In this review, we will pay particular attention to the host cell-cell communication events occurring downstream of programmed cell death and highlight new research and new questions surrounding how these fundamental host processes interact with the bacterial communities, with a particular focus on the intestine and the lung.

Keywords:  Apoptosis; Bacteria; Host-microbe interactions; Metabolism

DOI:  https://doi.org/10.1007/978-3-031-92785-0_7
Adv Exp Med Biol. 2025 ;1481 293-303

Entosis in Health and Disease.

Jyotirekha Das, Michael Overholtzer.

  Entosis is a mechanism of cell-in-cell formation that resembles phagocytosis but is regulated by distinct processes related to cell-cell adhesion and actomyosin tension. Entosis results in the engulfment of cells with high levels of tension, which become internalized into cells with lower tension, following the formation of adherens junctions between the pair. The resulting "cell-in-cell" structures typically resolve in a manner that leads to the death of the internalized cells, although other fates, including internalized cell release, are also possible. Entosis is induced in response to a variety of stressors, sometimes in parallel to other forms of cell death, and has been observed to occur in cancer as well as normal tissues. Here we discuss the mechanism of entosis and consider its unique properties compared to other forms of cell death and engulfment.

Keywords:  Adherens junctions; Autophagy; E-cadherin; Entosis; Entotic cell death; Lysosome; ROCK; Rho

DOI:  https://doi.org/10.1007/978-3-031-92785-0_9
Nat Chem. 2025 Sep 26.

Live-cell imaging with fluorogenic radical-trapping antioxidant probes reveals the onset and progression of ferroptosis.

Laiyi Xu, Wenzhou Zhang, Juan F Sánchez Tejeda, Denys Holovan, Julia McCain, Terri C Lovell, Gonzalo Cosa.

Ferroptosis is a form of cell death involving the formation of lipid peroxyl radicals, with potential therapeutic applications. Sensitivity to ferroptosis is expected to vary in different organelles. To monitor in real time the onset and progression of lipid peroxidation in ferroptosis, here we report lipophilic fluorogenic radical-trapping antioxidants, embedding in endoplasmic reticulum, lysosomes, mitochondria and plasma membrane. We show that endoplasmic reticulum- and lysosome-embedding fluorogenic radical-trapping antioxidants are most effective in protecting from cell death. The onset of lipid peroxidation happens in the endoplasmic reticulum, with lipid hydroperoxide accumulating in Golgi-associated vesicles. Disintegration of these structures spreads lipid hydroperoxide intracellularly, acting as 'free radical embers'. Outwards migration of oxidized lipids to plasma membrane, the ultimate sink for oxidized lipids, was recorded. Our results underscore Golgi-associated structures as a site to regulate ferroptosis progression. The work further positions fluorogenic radical-trapping antioxidants as valuable tools for unravelling the dynamic subcellular progression of ferroptosis.

DOI: https://doi.org/10.1038/s41557-025-01966-x