bims-traimu 2025-11-16 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2025–11–16
sixteen papers selected by
Yantong Wan, Southern Medical University

Innate immune memory: The evolving role of macrophages in therapy.
Diet and Trained Immunity in Cardiovascular Diseases.
Trained Immunity in Health and Disease.
Leveraging Mycobacterium tuberculosis Rv1507A Protein for Improved Immunogenicity in Mycobacterium bovis BCG Vaccine.
IRF7 drives macrophages to kill bacteria and improves septic outcomes via autophagy.
Endothelial cells retain inflammatory memory through chromatin remodeling in a two-hit model of infection-induced inflammation.
COVID-19 Hijacking of the Host Epigenome: Mechanisms, Biomarkers and Long-Term Consequences.
Mechanisms of Innate Immune Modulation by High-Fat Diet: Implications for Obesity and Asthma.
Gut-primed neutrophils activate Kupffer cells to promote hepatic injury in mouse sepsis.
Innate Immunity Disorders in Non-Infectious Inflammatory Diseases.
Single-cell transcriptomic analysis reveals immune remodeling in bone marrow during aged sepsis.
The Hippo Kinases MST1/2 Integrate Sterile and Infectious Signals to Regulate Macrophage Cell Death.
Exploring the concept of bacterial memory.
Genetic and Epigenetic Phenomena in the Neutrophil Developmental Program.
Cross-species blood transcriptional correlates of BCG-mediated protection against tuberculosis include innate and adaptive immune processes.
A glucose kinase-independent HK2 activity prevents TNF-induced cell death by phosphorylating RIPK1.

Elife. 2025 Nov 14. pii: e108276. [Epub ahead of print]14

Innate immune memory: The evolving role of macrophages in therapy.

Payal Damani-Yokota, Kamal Mohan Khanna.

  Trained immunity is reshaping our understanding of host defense by demonstrating that innate immune cells once thought to lack memory can be reprogrammed to mount heightened responses to subsequent challenges. Unlike tolerance, differentiation, or priming, trained immunity relies on epigenetic and metabolic rewiring of resident myeloid cells, particularly in mucosal barriers such as the skin, gut, and lungs, where these cells provide continuous protection against toxins and pathogens. Here, we review recent advances showing how an initial stimulus endows monocytes and macrophages with long-lasting functional changes that can be either protective or maladaptive upon re-exposure. We highlight therapeutic opportunities that harness trained immunity to boost vaccine efficacy and discuss strategies to modulate this program in cancer and hyper-inflammatory disorders. Finally, we propose new directions for enhancing or dampening trained immunity to promote human health.

Keywords:  bone marrow; immunology; infection; infectious disease; inflammation; innate immune memory; innate immunity; lung; macrophage; microbiology; monocyte; trained immunity

DOI:  https://doi.org/10.7554/eLife.108276
Arterioscler Thromb Vasc Biol. 2025 Nov 13.

Diet and Trained Immunity in Cardiovascular Diseases.

Niels P Riksen, Quirijn de Mast.

  Innate immune cells can develop a long-lasting hyperresponsive phenotype by metabolic and epigenetic reprogramming after brief exposure to inflammatory stimuli. Several experimental studies convincingly demonstrated that this immunologic phenomenon, which is called trained immunity, can accelerate the development of atherosclerosis. In this brief review, we summarize current evidence that diets and specific dietary components can modulate trained immunity. In mice, intermittent high-fat diets can reprogram bone marrow myeloid progenitor cells, resulting in hyperinflammatory monocytes and neutrophils that aggravate atherosclerosis. Diet-induced obesity also leads to persistent proinflammatory epigenetic reprogramming of myeloid cells and adipocytes. Hyperglycemia and high-salt diets can also induce trained immunity in murine models. Recent intervention studies in Tanzania revealed that urban Western-style diets trigger systemic inflammation and immune activation, whereas a traditional plant-based heritage diet limits inflammation. Ex vivo studies suggest that this is caused, at least in part, by modulation of trained immunity. Various individual dietary components, such as the flavone apigenin and the polyphenol resveratrol, are able to prevent trained immunity in vitro. It is exciting to speculate how further molecular elucidation on the modulation of trained immunity by diets or isolated dietary components could help to prevent cardiovascular diseases.

Keywords:  atherosclerosis; cardiovascular diseases; diet, high-fat; myeloid progenitor cells; trained immunity

DOI:  https://doi.org/10.1161/ATVBAHA.125.322608
MedComm (2020). 2025 Nov;6(11): e70461

Trained Immunity in Health and Disease.

Meng Yao, Jian Zhou, Jialun Mei, Chuan Gao, Peng Ding, Gan Li, Changqing Zhang, Zhiwei Li, Junjie Gao.

  Trained immunity as a critical regulator of host defense and disease pathogenesis bridges the gap between innate and adaptive immunity. For decades, the classic dichotomy of innate immunity and adaptive immunity has shaped our knowledge of immune function. Innate immunity has traditionally been regarded as a rapid, nonspecific first line of defense without memory capacity, while adaptive immunity is characterized by slower, antigen-specific responses and long-term immune memory. However, emerging evidence that innate immunity exhibits memory-like properties challenges the paradigm. Basically, innate immune cells with nonspecific memory retain functional imprints of prior encounters with diverse stimuli. Here, we comprehensively explore the intricate molecular and cellular mechanisms that underpin trained immunity, encompassing epigenetic inheritance, metabolic reprogramming, and transcriptional rewiring. Its dual roles are highlighted in health and disease. On one hand, it bolsters host defense against a broad spectrum of pathogens from bacteria to viruses, and enhances vaccine efficacy through heterologous protection. On the other hand, its dysregulation contributes to infection, inflammation, and cancer progression. As for the promising opportunities on therapeutic intervention, the challenges in precisely modulating trained immunity are tackled to offer a holistic perspective on the dynamically evolving field.

Keywords:  epigenetic inheritance; immune cells; immunotherapy; metabolic reprogramming; trained immunity

DOI:  https://doi.org/10.1002/mco2.70461
Immunology. 2025 Nov 08.

Leveraging Mycobacterium tuberculosis Rv1507A Protein for Improved Immunogenicity in Mycobacterium bovis BCG Vaccine.

Nilofer Naqvi, Anwar Alam, Mohd Shariq, Yashika Ahuja, Dipendra K Mitra, Seyed E Hasnain, Nasreen Z Ehtesham.

  Tuberculosis (TB) remains a global health burden, particularly because of the limited efficacy of the Bacillus Calmette-Guérin (BCG) vaccine against adult pulmonary TB. To improve immunogenicity, we developed a recombinant BCG strain expressing the M. tuberculosis-specific antigen Rv1507A (rBCG_Rv1507A) and evaluated its immune-enhancing potential. rBCG_Rv1507A-infected human PBMCs and murine macrophages exhibited enhanced co-stimulatory marker expression and Th1-skewed cytokine profiles in vitro. The vaccine stimulated the expansion of T follicular helper (TFH) cells and both central and effector memory T cells. Intratracheal immunisation induced systemic and mucosal antibody responses, localized memory B cell formation, and enrichment of lung-resident memory T cells in vivo. Importantly, rBCG_Rv1507A promoted macrophage apoptosis and suppressed autophagy, which may support cross-antigen presentation. Furthermore, it induces features of trained immunity, including hematopoietic progenitor expansion and metabolic reprogramming of macrophages. These immunological enhancements were compartmentalized to the lungs, the primary site of TB infection, due to mucosal delivery. Collectively, rBCG_Rv1507A demonstrated potential as a next-generation TB vaccine by integrating durable adaptive memory with innate immune training. However, further studies are required to confirm its protective efficacy.

Keywords:  adaptive immune response; antibody‐mediated immunity; antigen presentation; cell‐mediated immunity; innate immune response; memory response; trained immunity

DOI:  https://doi.org/10.1111/imm.70063
JCI Insight. 2025 Nov 10. pii: e189420. [Epub ahead of print]10(21):

IRF7 drives macrophages to kill bacteria and improves septic outcomes via autophagy.

Guiming Chen, Kangxin Li, Haihua Luo, Lianxu Zhao, Yong Jiang.

  Sepsis contributes substantially to mortality rates worldwide, yet clinical trials that have focused on its underlying pathogenesis have failed to demonstrate benefits. Recently, enhancing self-defense has been regarded as an emerging therapeutic approach. Autophagy is a self-defense mechanism that protects septic mice, but its regulatory factor is still unknown. Moreover, the role of interferon regulatory factor 7 (IRF7) in sepsis has been debated. Here, we showed that Irf7 deficiency increased mortality during polymicrobial sepsis. Furthermore, IRF7 drove macrophages to protect against sepsis. Mechanistically, IRF7 is a transcription factor that upregulates the expression of autophagy-related genes responsible for autophagosome formation and autolysosome maturation, induces autophagic killing of bacteria, and ultimately reduces septic organ injury. Recombinant adeno-associated virus 9-Irf7-mediated IRF7 overexpression promoted the autophagic clearance of pathogens and improved sepsis outcomes, which may be the mechanism underlying the observed improvement in bacterial clearance. These findings provide evidence that IRF7 is the underlying regulatory factor that drives autophagy to eliminate pathogens in macrophages during sepsis. Collectively, IRF7 overexpression represents a potential host-directed therapeutic strategy for preclinical sepsis models, operating independently of antibiotic mechanisms.

Keywords:  Autophagy; Bacterial infections; Infectious disease; Macrophages; Therapeutics

DOI:  https://doi.org/10.1172/jci.insight.189420
Am J Physiol Cell Physiol. 2025 Nov 11.

Endothelial cells retain inflammatory memory through chromatin remodeling in a two-hit model of infection-induced inflammation.

Daniel Gonsales Spindola, Amber Bahr, Samantha Clark, Gabriel Pin de Jesus, Nina Martino, Anthony Lowery, Shuhan Lyu, Andrew Seeman, Grace Martino, Giesse Albeche Duarte, Elijah Crosbourne, Peter Vincent, Guangchun Bai, Alejandro P Adam, Katherine C MacNamara, Ramon Bossardi Ramos.

  Sepsis survivors face a heightened risk of secondary infections following discharge, yet the underlying mechanisms remain poorly defined. Our study identifies a novel mechanism of endothelial inflammatory memory, wherein inflammatory exposure induces durable chromatin remodeling in endothelial cells, priming them for exaggerated responses to a subsequent infection. Utilizing a clinically relevant two-hit mouse model, cecal ligation and puncture (CLP) followed by mild Streptococcus pneumoniae (Sp) infection in CLP survivors, we reveal transcriptional activation in endothelial cells (ECs) following secondary infection, marked by significantly elevated expression of pro-inflammatory cytokines, adhesion molecules, complement factors, and interferon-stimulated genes. Genome-wide ATAC-seq revealed that a subset of inflammatory gene loci retained increased chromatin accessibility even after cytokine withdrawal, demonstrating stable epigenetic remodeling consistent with transcriptional priming and inflammatory memory. In vitro, we uncovered a critical role for the AP-1 transcription factor JunB in mediating this epigenetic remodeling. JunB knockdown attenuated chromatin accessibility after an initial IL-6 challenge and subsequent transcriptional amplification upon a secondary LPS challenge, pinpointing JunB-driven chromatin modifications as central to endothelial reprogramming. Our findings offer mechanistic insights into how transient inflammation creates lasting epigenetic states within the endothelium, highlighting JunB as a potential therapeutic target to mitigate chronic endothelial dysfunction and increased susceptibility to secondary infections post-sepsis.

Keywords:  Chromatin; Endothelium; Inflammation; Inflammatory memory; Sepsis

DOI:  https://doi.org/10.1152/ajpcell.00567.2025
Int J Mol Sci. 2025 Oct 24. pii: 10372. [Epub ahead of print]26(21):

COVID-19 Hijacking of the Host Epigenome: Mechanisms, Biomarkers and Long-Term Consequences.

Alena D Zolotarenko, Hakob M Poghosyan, Victoria V Sheptiy, Sergey A Bruskin.

  The epigenetics of COVID-19 is a rapidly expanding field that reveals how the SARS-CoV-2 virus initiates alterations in the host's genome, influencing the susceptibility to infection, the disease severity, and long-term consequences, known as "long COVID." In this review, we describe the mechanisms utilized by the virus to manipulate the host epigenome, suppressing antiviral responses and creating a favorable environment for viral replication. We also highlight virus-induced epigenetic changes across diverse cell populations that contribute to COVID-19 pathogenesis. Notably, the virus reprograms hematopoietic stem and progenitor cells, leading to long-lasting alterations in innate immunity, a phenomenon known as "trained immunity." These epigenetic modifications are maintained in differentiated daughter cells and may explain the persistent inflammation and other symptoms of long COVID. Furthermore, we discuss emerging epigenetic biomarkers of disease severity, including methylation signatures in genes such as AIM2, HLA-C, and PARP9, as well as dysregulated miRNA profiles. Understanding this complex interplay between the virus and the host's epigenetic landscape is crucial for developing new therapeutic approaches that target specific epigenetic modifications to suppress pathological processes and improve clinical outcomes for COVID-19 patients.

Keywords:  COVID-19; epigenetics; epimarkers of disease severity; long COVID; trained immunity; viral hijacking

DOI:  https://doi.org/10.3390/ijms262110372
Curr Allergy Asthma Rep. 2025 Nov 10. 25(1): 51

Mechanisms of Innate Immune Modulation by High-Fat Diet: Implications for Obesity and Asthma.

Heather L Caslin, Jesse W Williams.

   PURPOSE OF THE REVIEW: The innate immune system plays a critical role in mediating many of the physiological consequences of high-fat diet consumption. Dietary lipids, and specifically saturated fatty acids like palmitate and stearate, directly activate innate immune cells and alter the composition of the gut microbiome. Moreover, long-term high-fat diet feeding can induce chronic inflammation, adipose expansion, and the development of obesity. High-fat diet consumption and obesity also worsen the risk for chronic diseases like asthma.
RECENT FINDINGS: It is well known that high-fat diet feeding activates innate immune cells and alters the gut microbiome. However, emerging research provides new insight into the mechanisms by which high-fat diet feeding and obesity affect innate immunity and further disease development. These emerging mechanisms include the induction of lipid-associated macrophages (LAMs), innate immune memory, and innate-adaptive crosstalk leading to T cell exhaustion and granzyme K production. These novel mechanisms help us better understand the effect of high-fat diets on innate immunity, and future studies in these areas may help us better identify new therapeutic strategies for managing obesity and asthma.

Keywords:  Allergic disease; Immunometabolism; Metabolic disease; Trained innate immunity; Weight loss

DOI:  https://doi.org/10.1007/s11882-025-01232-7
Nat Commun. 2025 Nov 10. 16(1): 9657

Gut-primed neutrophils activate Kupffer cells to promote hepatic injury in mouse sepsis.

Atsushi Murao, Alok Jha, Takayuki Kato, Junji Shimizu, Yuichi Akama, Monowar Aziz, Ping Wang.

Sepsis-induced liver injury is common, but the underlying mechanisms remain poorly understood. Given the critical role of gut-liver crosstalk in sepsis, we hypothesize that gut-trained neutrophils, migrating via the portal vein, release neutrophil extracellular traps (NETs) to activate Kupffer cells, thereby exacerbating hepatic injury during sepsis. Here we show that iNOS expression in Kupffer cells increases in septic wild type mice but decreases in PAD4-/- mice. In vitro, NETs stimulate Kupffer cell IL-6 and TNF release, while conditioned media from NET-treated Kupffer cells induces hepatocyte death. Inhibition of neutrophil elastase and protease-activated receptor-1 (PAR-1) mitigates IL-6 and TNF secretion by Kupffer cells. Ex vivo, portal vein neutrophils from septic mice produce more NETs and induce greater Kupffer cell activation than systemic neutrophils, with this effect attenuated in PAD4-/- neutrophils. Furthermore, gut intraepithelial lymphocytes (IELs) interact with neutrophils during sepsis and facilitate NETosis, and IEL-primed neutrophils also induce Kupffer cell activation in vitro and in vivo. Our data thus suggest that IEL-facilitated, gut-derived neutrophil NETs activate Kupffer cells to contribute to sepsis-induced liver injury.

DOI: https://doi.org/10.1038/s41467-025-65572-8
Curr Med Chem. 2025 Nov 14.

Innate Immunity Disorders in Non-Infectious Inflammatory Diseases.

Nikita G Nikiforov.



Keywords:  Innate immunity; PADI2; PADI4; atherosclerosis; citrullination; cyclin-dependent kinases (CDKs); glycolysis; immunometabolism; inflammation regulation.; macrophages; nitric oxide; sterile inflammation

DOI:  https://doi.org/10.2174/0109298673453799251030181811
Geroscience. 2025 Nov 12.

Single-cell transcriptomic analysis reveals immune remodeling in bone marrow during aged sepsis.

Yijia Lin, Zhiying Zhou, Mingkun Yang, Yingzheng Weng, Zhouxin Yang, Jing Yan.

  Aging substantially increases susceptibility to sepsis, yet the underlying mechanisms of immune dysfunction in the elderly remain incompletely understood. Polymicrobial sepsis was induced in young and aged male mice via cecal ligation and puncture (CLP). Bone marrow from four groups (Y-Sham, n = 2; Y-CLP, n = 3; A-Sham, n = 2; A-CLP, n = 3) was analyzed by single-cell RNA sequencing and intercellular communication inferred via CellChat. Age-related immune changes were evaluated, and Transwell assays were used to assess myeloid cell migration. Aged septic mice showed worsened organ damage and systemic inflammation, with reduced adaptive (18.7% vs. 41.3%) and increased innate immunity (58.8% vs. 37.7%, A-CLP vs. Y-CLP). Neutrophil chemotaxis was impaired; monocytes and macrophages adopted a hyperinflammatory yet functionally exhausted phenotype; dendritic cells showed increased antigen presentation with diminished mobility; B cell maturation was disrupted with regression to earlier developmental stages; and T cells shifted toward stress-responsive and regulatory programs. We identified a cluster-specific expansion of HSCs in aged sepsis (39.8% vs. 31.2% in A-CLP vs. Y-CLP) with impaired Lgals9-Cd44-mediated intercellular communication. Myeloid cell migration was impaired in A-CLP but partially restored by Lgals9-Cd44 activation. This study presents a comprehensive single-cell map of bone marrow immune dysfunction in aged sepsis and identifies impaired HSC-myeloid communication as a critical mechanism driving immune failure. Therapeutically targeting the Lgals9-Cd44 axis may restore immune coordination in elderly sepsis, although its clinical feasibility and safety remain to be validated.

Keywords:  Aging; Bone marrow; Hematopoietic stem cells; Immunosenescence; Sepsis; Single-cell RNA sequencing

DOI:  https://doi.org/10.1007/s11357-025-01966-2
J Biol Chem. 2025 Nov 07. pii: S0021-9258(25)02772-3. [Epub ahead of print] 110920

The Hippo Kinases MST1/2 Integrate Sterile and Infectious Signals to Regulate Macrophage Cell Death.

Sydney M Quagliato, Matthew Gulker, Ryan Mirhosiny, Lucas Meints, Brendyn M St Louis, Yu-Ting Su, Fangyuan Sun, Yuan He, Pei-Chung Lee.

  Mammalian STE20-like kinases MST1 and MST2 are the conserved Hippo kinases known for their importance in organ development and tumor suppression. Notably, humans and mice lacking these kinases have increased susceptibility to infection, indicating a role of MST1/2 in immunity. In macrophages that are critical immune cells in host defense, MST1/2 are proteolytically cleaved to coordinate different forms of programmed cell death, including apoptosis and pyroptosis. This cleavage event occurs when the innate immune sensors, inflammasomes, are activated by the bacterial pathogen, Legionella pneumophila, or damage-associated molecular patterns. In this report, we examine MST1/2 cleavage in macrophages under various inflammatory conditions and challenges with pathogenic bacteria. ATP and nigericin induce MST1/2 cleavage and apoptosis, while the NLRP3 inflammasome and GSDMD-mediated pyroptosis are activated. Remarkably, in conditions that do not support activation of NLRP3 or GSDMD, MST1/2 are still cleaved by caspases to promote cell death in macrophages treated with these molecules. During infection, wildtype macrophages trigger MST1/2 cleavage and apoptosis against L. pneumophila and Yersinia pseudotuberculosis but preferentially activate GSDMD-mediated pyroptosis against Pseudomonas aeruginosa. Interestingly, GSDMD knockout macrophages opt to cleave MST1/2 and undergo apoptosis in response to P. aeruginosa, suggesting an interplay between GSDMD and MST1/2. Together, macrophages funnel apoptotic death signals through MST1/2 cleavage upon stimulation of the inflammatory molecules and pathogens, illustrating the broad implications of the host Hippo kinases in infections and inflammation.

Keywords:  bacterial pathogenesis; cysteine protease; host defense; post‐translational modification (PTM); proteolysis

DOI:  https://doi.org/10.1016/j.jbc.2025.110920
Nat Microbiol. 2025 Nov 14.

Exploring the concept of bacterial memory.

Killian Scanlon, Fergus Shanahan, R Paul Ross, Colin Hill.

Bacteria have multiple mechanisms through which they sense changes in their environment and respond appropriately. In some instances, bacteria appear to retain an imprint of past events that can influence future behaviour, resembling a form of memory. This Perspective explores this concept of bacterial memory at the genetic, epigenetic, biochemical and ecological levels. We discuss how memory can prime bacteria to respond appropriately to recurring stimuli, providing fitness benefits in fluctuating environments. At the cellular level, there is evidence for memory storage mechanisms involving mutations, DNA methylation, or the inheritance of metabolites or proteins that provide a means of accessing past experiences. Complex bacterial communities can exhibit ecological memories of past environments, stored as microbiota population changes that persist or lag after acute environmental change. We review the emerging evidence supporting these concepts of microbial memory, outline some of the key molecular mechanisms, and identify research gaps and potential future applications.

DOI: https://doi.org/10.1038/s41564-025-02185-3
Int J Immunogenet. 2025 Nov 09. e70025

Genetic and Epigenetic Phenomena in the Neutrophil Developmental Program.

Milena N Leseva, Petya A Dimitrova.

  Neutrophils are short-lived innate immune cells, which develop in the bone marrow and replenish daily the circulatory and marginal pools in various organs in the steady state. Recent technological advances have reshaped the traditional paradigms for neutrophil biology and have identified intriguing (epi)genetic phenomena associated with their differentiation, maturation and function. Herein we summarise these developments and discuss: the new model for instructed programming of neutrophil development and continuous cell development via the lineage trajectory path; new aspects of epigenetic regulation of neutrophil development and in particular changes in chromatin structure, 3D architecture as well as heterochromatin condensation during nuclear segmentation; the remarkable breadth of neutrophil heterogeneity and the atypical function of neutrophils acting as antigen-presenting cells. Understanding these concepts can advance the design of new models of in vitro neutrophil generation and drug discovery in immune-mediated disease and cancer where neutrophils play important roles in the pathogenesis.

Keywords:  chromatin architecture; chromatin structure; development; differentiation; effector function; epigenetic modifications; maturation; neutrophils; paradigm; transcriptional trajectory

DOI:  https://doi.org/10.1111/iji.70025
JCI Insight. 2025 Nov 11. pii: e194450. [Epub ahead of print]

Cross-species blood transcriptional correlates of BCG-mediated protection against tuberculosis include innate and adaptive immune processes.

Kate Bridges, Denis Awany, Anele Gela, Temwa-Dango Mwambene, Sherry L Kurtz, Richard E Baker, Karen L Elkins, Christopher M Sassetti, Thomas J Scriba, Douglas A Lauffenburger.

  The immune mechanisms induced by the Bacillus Calmette-Guérin (BCG) vaccine, and the subset of which mediate protection against tuberculosis (TB), remain poorly understood. This is further complicated by difficulties to verify vaccine-induced protection in humans. Although research in animal models, namely mice and non-human primates (NHPs), has begun to close this knowledge gap, discrepancies in the relative importance of biological pathways across species limit the utility of animal model-derived biological insights in humans. To address these challenges, we applied a systems modeling framework, Translatable Components Regression (TransCompR), to identify human blood transcriptional variability which could predict Mtb challenge outcomes in BCG-vaccinated NHPs. These protection-associated pathways included both innate and adaptive immune activation mechanisms, along with signaling via type I interferons and anti-mycobacterial T helper cytokines. We further partially validated the associations between these mechanisms and protection in humans using publicly available microarray data collected from BCG-vaccinated infants who either developed TB or remained healthy during two years of follow-up. Overall, our work demonstrates how species translation modeling can leverage animal studies to generate hypotheses about the mechanisms that underlie human infectious disease and vaccination outcomes, which may be difficult or impossible to ascertain using human data alone.

Keywords:  Bacterial vaccines; Cellular immune response; Immunology; Infectious disease; Tuberculosis

DOI:  https://doi.org/10.1172/jci.insight.194450
Nat Commun. 2025 Nov 13. 16(1): 9979

A glucose kinase-independent HK2 activity prevents TNF-induced cell death by phosphorylating RIPK1.

Tianhao Zou, Ran Liu, Gengqiao Wang, Guoliang Wang, Zhengting Jiang, Chuanzheng Wang, Weimin Wang, Mao Cai, Shuhua Zhang, Huan Cao, Di Zhang, Xueling Wang, Shenghe Deng, Tongxi Li, Jinyang Gu.

Tumor necrosis factor (TNF)-induced RIPK1-mediated cell death is implicated in various human diseases. However, the mechanisms RIPK1-mediated cell death is regulated by metabolic processes remain unclear. Here, we identify hexokinase 2 (HK2), a critical regulator of glycolysis, as a suppressor of TNF-induced RIPK1 kinase-dependent cell death through its non-metabolic function. HK2 inhibits RIPK1 kinase activity through constitutively phosphorylation at serine 32 of RIPK1. Inhibition of RIPK1 S32-phosphorylation results in RIPK1 kinase activation and subsequent cell death in response to TNFα stimulation. We further show that HK2 is elevated under pathological conditions including liver ischemia-reperfusion (IR) injury and hepatocellular carcinoma (HCC) via the transcriptional factor HMGA1. Moreover, the upregulation of HK2 in the liver confers protection against liver IR injury mediated by RIPK1 kinase, while depleting HK2 in HCC cells enhances TNFα-induced cell death and synergistically improves the efficacy of anti-PD1 therapy in an HCC model. Thus, the findings reveal a potential therapeutic avenue for RIPK1-related diseases through manipulating HK2 non-metabolic function.

DOI: https://doi.org/10.1038/s41467-025-64939-1