bims-traimu Biomed News
on Trained immunity
Issue of 2026–08–16
fourteen papers selected by
Yantong Wan, Southern Medical University
  1. The long shadow of a short life: How neutrophils confer trained immunity.
  2. How the microbiome shapes epigenetic trained memory in neuroinflammation: Implications for neurodegenerative diseases.
  3. Trained immunity in autoinflammatory diseases: Cellular reprogramming across the monogenic-polygenic spectrum.
  4. Innate immune reprogramming of chicken macrophages by sodium butyrate enhances reactive oxygen species-mediated antimicrobial responses in vitro.
  5. Epithelial-Dermal Immune Memory: Tracking Staphylococcus aureus-Induced Trained Immunity in the Progression of Chronic Skin Inflammation.
  6. New vaccine strategies targeting cellular and trained immunity against intracellular bacteria in fish.
  7. β-glucan elicits APOE-dependent peripheral trained immunity to suppress hepatocellular carcinoma.
  8. Maladaptive trained immunity as a hematopoietic stem cell driver of inflammaging.
  9. IRF1 mediates airway epithelial innate memory through priming BRD4- EP300 activity.
  10. Author Correction: Trained immunity links hematopoietic stem cell aging to aging-associated inflammation.
  11. BCG-induced trained immunity on clinical outcomes in moderate to severe COVID-19 patients at a tertiary care center: A comparative study based on interferon-gamma release assays status.
  12. Genetic analysis of inflammatory proteins following BCG vaccination in Danish children.
  13. Multi-level transcriptional control of specific macrophage responses.
  14. An epigenetic switch in β-cells links mitochondrial stress to inflammatory fate via HMGB1 acetylation.
  1. Autoimmun Rev. 2026 Aug 12. pii: S1568-9972(26)00178-3. [Epub ahead of print]25(11): 104164
    The long shadow of a short life: How neutrophils confer trained immunity.
    Fumei Liu, Jiatong Chai, Peini Yang, Shiyu Fu, Xingrong Li, Xinli Jiang, Yumei Li, Tianxiang Ji, Yihan Fu, Huan Hu, Jianyong Zhou, Rongxia Guo, Yirong Li.
      Neutrophils, traditionally viewed as short-lived, terminally differentiated innate immune cells with no capacity for immunological memory, have recently been recognized as key players in trained immunity. This concept challenges the classical dichotomy between innate and adaptive immunity by demonstrating that prior microbial or inflammatory stimuli can induce long-lasting functional reprogramming of innate immune cells. This review provides a comprehensive overview of neutrophil-trained immunity, covering the central role of the bone marrow niche in storing innate immune memory, the epigenetic and metabolic mechanisms that underpin training, the diverse triggers (microbial ligands, vaccines, and endogenous sterile inducers), and the resulting functional consequences in neutrophils. Crucially, this response operates on a dose-dependent polarity: low-dose priming induces protective memory, whereas chronic or excessive inflammatory stimuli trigger neutrophil exhaustion and persistent tissue injury. We argue that the classical paradigm of autoantibody-driven tissue damage in autoimmune conditions is fundamentally anchored by "maladaptive trained immunity" established at the central hematopoietic level. Finally, this review discusses new strategies for the preparation of trained immunity-based vaccines and adjuvants, enhancement of immunity in immunocompromised patients, and clinical treatment to inhibit chronic inflammation, while also highlighting research gaps regarding the durability of neutrophil-trained immunity, the potential for de-training, and the interplay between trained immunity and other immune components, thereby revealing the significant implications and research prospects of neutrophil-trained immunity.
    Keywords:  Epigenetic reprogramming; HSPC; Metabolic rewiring; Neutrophil; Trained immunity
    DOI:  https://doi.org/10.1016/j.autrev.2026.104164
  2. J Neuroimmunol. 2026 Jul 30. pii: S0165-5728(26)00198-0. [Epub ahead of print]420 579049
    How the microbiome shapes epigenetic trained memory in neuroinflammation: Implications for neurodegenerative diseases.
    Mian Horvath, Jaime Imitola.
      Neurodegenerative diseases are increasingly recognized as disorders involving immune dysregulation. However, the mechanisms underlying this dysfunction remain poorly characterized. Trained immunity has recently emerged as a potential contributor to immune dysregulation, particularly in neuroinflammation and neurodegenerative diseases, where trained immunity is the epigenetic reprogramming of innate immune responses following an initial inflammatory stimulus, which increases responses to subsequent exposures. In parallel, although the brain has traditionally been viewed as an immune-privileged organ, growing evidence indicates that peripheral immune activity exerts significant influence on neuroinflammation in the brain. A major driver of peripheral immunity is the microbiome. Therefore, this perspective aims to present a conceptual framework for a relationship between the microbiome, trained immunity, and neurodegenerative diseases. We first summarize evidence of trained immunity in the brain and its role in neurodegeneration. Next, we highlight the role of the microbiome in peripheral immune modulation and in trained immunity. Finally, we propose potential mechanisms through which the microbiome may induce or modulate trained immunity in the brain. These include: 1) immunogenic microbial metabolites that cross the blood-brain barrier and alter host cell epigenetics; 2) migration of peripherally trained myeloid cells into the brain; 3) viral infection-induced trained immunity that may predispose to neurodegeneration. Together, this perspective suggests that microbiome-induced trained immunity offers a novel mechanism linking peripheral immune regulation with neuroinflammation and neurodegeneration with implications for therapeutic targeting of epigenetic modification as a molecular prevention strategy for progression of neurodegeneration.
    Keywords:  Inflammatory memory; Metabolites; Microbiome; Neurodegenerative disease; Trained immunity; Virome
    DOI:  https://doi.org/10.1016/j.jneuroim.2026.579049
  3. Eur J Cell Biol. 2026 Aug 11. pii: S0171-9335(26)00032-4. [Epub ahead of print]105(4): 151561
    Trained immunity in autoinflammatory diseases: Cellular reprogramming across the monogenic-polygenic spectrum.
    Ferenc Sipos, Györgyi Műzes.
      Trained immunity, an innate immunological memory induced by epigenetic and metabolic reprogramming, has changed the paradigm of host defense and pathogenesis of chronic inflammatory disease. Unlike adaptive immunological memory, trained immunity is characterized by the ability of innate immune cells and their progenitors to respond more robustly or differently to subsequent stimulations and contributes to chronic inflammatory conditions. Emerging data suggests that this process might be essential in autoinflammatory and immune-mediated inflammatory illnesses by enhancing sterile inflammation, decreasing activation thresholds, and boosting disease chronicity. This narrative review summarizes the existing evidence relating trained immunity to monogenic and polygenic autoinflammatory diseases. The greatest evidence in monogenic disease is for mevalonate kinase deficiency, where dysregulated mevalonate metabolism directly overlaps with conventional trained immunity pathways. Moderate evidence exists for familial Mediterranean fever, cryopyrin-associated periodic syndromes, and tumor necrosis factor receptor-associated periodic syndrome. For other rare hereditary autoinflammatory diseases, data are still inadequate. There is convincing evidence for a role of trained immunity in polygenic disorders like gout, atherosclerosis, obesity-associated "metaflammation", and type 2 diabetes and increasing evidence in Behçet's disease, adult-onset Still's disease, psoriasis, hidradenitis suppurativa, inflammatory bowel disease, and related inflammatory spectrum disorders. A major conceptual finding is that autoinflammatory illnesses may be a dynamic interplay between hereditary susceptibility and dysfunctional innate immune memory, rather than isolated static inflammatory abnormalities. However, information gaps still exist in reprogramming at the progenitor level, disease-specific epigenetic markers, and the reversibility of trained states. Understanding these systems may allow the development of therapeutic techniques to de-train abnormal innate immunological memory and obtain resilience for diseases.
    Keywords:  Autoinflammation; Epigenetics; Immunometabolism; Inflammasome; Innate memory; Reprogramming; Trained immunity
    DOI:  https://doi.org/10.1016/j.ejcb.2026.151561
  4. J Immunol. 2026 Aug 04. pii: vkag209. [Epub ahead of print]215(8):
    Innate immune reprogramming of chicken macrophages by sodium butyrate enhances reactive oxygen species-mediated antimicrobial responses in vitro.
    James R Adams, Faisal R Anjum, Muhammad Y Abare, Jai Mehat, Roberto L Ragione, Shahriar Behboudi.
      In the established model of classical trained immunity, metabolic and epigenetic hubs serve as central integrators of innate memory. While typically associated with proinflammatory reprogramming, the regulation of autophagy and cellular proteostasis remains essential for guiding macrophage differentiation and ensuring efficient pathogen clearance without excessive inflammation. In this study, we demonstrate that sodium butyrate (SB), a short-chain fatty acid, induces a functional profile that diverges from the canonical pathways observed in classical innate immune training. The induction of an innate reprogrammed state in chicken macrophages by SB is strictly dependent on the cellular developmental stage, occurring only during the early stages of differentiation from chicken bone marrow-derived macrophages but not in fully differentiated cells. This suggests that SB primarily facilitates an innate immune reprogramming with a specific temporal window of sensitivity. Our results show that SB-reprogrammed chicken macrophages exhibit enhanced reactive oxygen species generation, altered cytokine expression, and an increased capacity to kill a diverse range of bacteria. Treatment with chemical inhibitors further demonstrated that these heightened antibacterial effects are directly attributed to increased reactive oxygen species production and autophagy. In summary, these findings indicate that SB induces functional outcomes distinct from classical trained immunity and can elicit innate immune memory through alternative regulatory axes. Our data suggest that distinct innate reprogramming states give rise to alternative activation programs and that innate immune memory exists along a spectrum of phenotypes rather than as a single, uniform state.
    Keywords:  ROS; antimicrobial response; innate immune reprogramming; macrophages; reactive oxygen species; sodium butyrate
    DOI:  https://doi.org/10.1093/jimmun/vkag209
  5. Int J Mol Sci. 2026 Jul 28. pii: 6760. [Epub ahead of print]27(15):
    Epithelial-Dermal Immune Memory: Tracking Staphylococcus aureus-Induced Trained Immunity in the Progression of Chronic Skin Inflammation.
    Vidhya Prakash, Shivani Chalil Velluva, Shiv Shankar Sreekumar, Nidhi Jayaprakash, Nandana S Pillai, Noura Nizar, Nikita Arun, Kalyani Arun, Mohammed Aslam, Nidhisha Babysulatha Sasidharan, Parvathy Venugopal, Aparna Shankar, Bipin G Nair.
      The clinical paradigm distinguishing chronic atopic dermatitis (AD) from acute bacterial infections is established by the emerging evidence which focuses on persistent innate immune memory as a central pathobiological factor mediating inflammatory skin diseases. While AD is classically defined by genetic susceptibility and epidermal barrier failure, progression of deep dermal Staphylococcus aureus invasion, which is characteristic of bacterial infections like cellulitis, implies a significant acute infectious condition resulting in significant tissue damage, which drives extensive innate immune reprogramming. Recent studies have established a bidirectional relationship between these conditions, yet the underlying molecular mechanisms remain undefined. However, trained immunity, governed by epigenetic and metabolic reprogramming, has now emerged as a critical mediator of this interaction. This review attempts to explore the molecular foundations of trained immunity as a mechanistic link between acute infectious conditions and chronic skin inflammation. The critical involvement of bacterial virulence factors and pattern recognition receptor signalling pathways, which instigate persistent innate memory, predisposes the tissue to recurrent infections and aggravated inflammatory responses. Furthermore, the persistent involvement of innate immune reprogramming in facilitating a mechanistic continuum between cellulitis and chronic dysregulation, characteristic of atopic dermatitis, is discussed. In continuum, we propose emphasising emerging therapeutic strategies targeting epigenetic checkpoints and metabolic rewiring to develop novel immunomodulatory interventions to combat infectious and inflammatory skin disorders.
    Keywords:  atopic dermatitis; cellulitis; chromatin accessibility; epigenetic reprogramming; short-chain fatty acids; trained immunity
    DOI:  https://doi.org/10.3390/ijms27156760
  6. Fish Shellfish Immunol. 2026 Aug 10. pii: S1050-4648(26)00546-2. [Epub ahead of print]178 111642
    New vaccine strategies targeting cellular and trained immunity against intracellular bacteria in fish.
    Esteban A Valdebenito, Susan M Bueno, Pablo A González, Alexis M Kalergis.
      The rapid growth of global aquaculture has led to an increase in infectious diseases, including intracellular bacterial pathogens such as Piscirickettsia salmonis and Edwardsiella spp., which threaten the industry's sustainability. These microbial agents evade humoral immunity by replicating inside host cells, making traditional inactivated vaccines largely ineffective because they do not generate strong cell-mediated immunity (CMI) or trained immunity. Here, we revisit and analyze emerging strategies aimed at stimulating CMI and inducing trained immunity in fish, explaining their mechanisms and their potential to control intracellular infections. We also examine the use of in silico platforms to identify antigens that activate cellular pathways, followed by advanced delivery and expression methods such as nanolipids (LNPs) and recombinant bacteria such as Bacillus Calmette-Guérin (BCG). Additionally, we explore trained immunity, the epigenetic and metabolic reprogramming of innate immune cells, as a complementary approach for broad-spectrum protection. Lastly, we highlight the need to redefine vaccine efficacy by including functional memory parameters beyond traditional antibody titers and survival rates. By integrating these advances, this review assesses innovative platforms that could transform disease control and decrease reliance on antibiotics in modern aquaculture.
    Keywords:  Aquaculture; Cellular immunity; Fish; Intracellular bacteria; Trained immunity; Vaccines
    DOI:  https://doi.org/10.1016/j.fsi.2026.111642
  7. J Immunother Cancer. 2026 Aug 04. pii: e015401. [Epub ahead of print]14(8):
    β-glucan elicits APOE-dependent peripheral trained immunity to suppress hepatocellular carcinoma.
    Nan Jiang, Tong Wu, Rensheng Yang, Guijin He, Bo Ding, Can Zhu, Hanqing Liu, Xinyu Xu, Beng Yang, Haiyang Xie, Shusen Zheng, Rongliang Tong, Jian Wu.
       BACKGROUND: Although immunotherapy has revolutionized cancer treatment, hepatocellular carcinoma (HCC) continues to demonstrate limited clinical responses, highlighting the urgent need for novel immunomodulatory strategies. Trained immunity, an emerging paradigm wherein innate immune cells develop a memory-like phenotype through epigenetic and metabolic reprogramming, offers a promising avenue to remodel the immunosuppressive tumor microenvironment. This study investigated whether β-glucan-induced trained immunity could potentiate antitumor immunity against HCC.
    METHODS: We established orthotopic HCC mouse models to investigate the role of trained immunity induced by whole β-glucan particle (WGP) in the HCC microenvironment, particularly in modulating hepatic apolipoprotein E (APOE)-positive monocytes/macrophages. Transcriptional changes in trained monocytes/macrophages were identified by analyzing single-cell RNA sequencing and bulk RNA-sequencing data from the livers of WGP-treated and control mice. Mechanistic studies were performed using Apoe -/- mice and in situ monocyte/macrophage engineering. Flow cytometry was performed to assess immune cell phenotypes and phagocytosis, while luminescence-based assays were used to evaluate cytotoxic activity. The translational potential was assessed using human monocyte training assays.
    RESULTS: This study demonstrated that preconditioning with WGP, a trained immunity inducer, increased the accumulation of trained monocytes/macrophages in the liver and suppressed tumor progression in HCC mouse models. Mechanistically, WGP-trained APOE+ monocytes/macrophages exhibited a decrease in lipid accumulation and endoplasmic reticulum stress, thereby enhancing their antitumor function. Genetic deletion of Apoe in monocytes/macrophages abrogated the antitumor effects of WGP, demonstrating that APOE+ monocytes/macrophages are essential mediators of WGP-induced trained immunity. Adoptive transfer of WGP-trained bone marrow-derived macrophages suppressed the growth of HCC in recipient mice. Furthermore, WGP induced trained immunity in human monocytes, leading to enhanced killing of HCC cells. Notably, combination therapy with WGP and anti-programmed death-ligand 1 antibody achieved superior tumor control compared with either monotherapy.
    CONCLUSIONS: These findings identify a critical role for trained APOE+ monocytes/macrophages in WGP-mediated antitumor immunity in the liver. Harnessing WGP-induced peripheral trained immunity represents a novel therapeutic strategy for HCC.
    Keywords:  Gene therapy; Hepatocellular Carcinoma; Immunotherapy; Innate; Myeloid
    DOI:  https://doi.org/10.1136/jitc-2026-015401
  8. Nat Aging. 2026 Aug 10.
    Maladaptive trained immunity as a hematopoietic stem cell driver of inflammaging.
    Maziar Divangahi, Katherine Y King.
      
    DOI:  https://doi.org/10.1038/s43587-026-01197-w
  9. Front Immunol. 2026 ;17 1923234
    IRF1 mediates airway epithelial innate memory through priming BRD4- EP300 activity.
    Xiaofang Xu, Robert L Gearhart, Monica Yun Liu, Allan R Brasier.
       Introduction: Sentinel cells of the airway epithelium are repetitively exposed to RNA virus infections. Here, the production of pathogen-associated molecular patterns (PAMPs) activates the innate immune response (IIR), inducing antiviral defenses, activating adaptive immunity and stimulating epithelial repair. The question whether repeated exposures produce innate "memory", where heightened inflammatory and injury/repair responses are produced upon subsequent exposure, is unknown.
    Methods: We establish a reproducible model of innate memory in tumor protein (TP63)+/keratin (KRT)5+ human small airway basal epithelial cells by repetitive activation of the Toll like receptor (TLR3) pathway (a.k.a. "training"). Mechanisms of IRF1-dependent target gene remodeling are investigated by CRISPR/Cas9 knockdown, chromatin immunoprecipitation, co-immunoprecipitation and through use of selective inhibitors of the BRD4 chromatin remodeling complex (CRC).
    Results: We observe "training" increases basal expression of a network of intrinsic IIR genes, reducing Respiratory Syncytial Virus (RSV) replication upon subsequent exposure. In addition, trained hSAECs enter an epithelial mesenchymal plasticity (EMP) program, characterized by cell shape changes, increased expression of cytoplasmic vimentin and core mesenchymal regulators. Mechanistically, we find that Interferon Regulatory Factor 1 (IRF1) is required for innate memory because IRF1-deficient cells fail to activate basal intrinsic IIR. In TLR3 activation, IRF1 is incorporated into the bromodomain containing protein 4 (BRD4) chromatin remodeling complex (CRC), a complex containing the histone H3 acetyltransferase, EP300/p300. In acute TLR3 activation, the binding of BRD4 is increased on intrinsic IIR promoters, yet this binding is unaffected by training. Instead, we find training induces EP300 binding and increases H3K27 acetylation (H3K27ac) at these regions. Small molecule inhibitors show that BRD4 is required for establishing innate memory and H3K27ac accumulation. Finally, we find that training enhances BRD4-EP300 interactions and that memory-induced H3K27ac formation is EP300-dependent.
    Conclusions: We conclude that hSAECs acquire innate memory through IRF1 coupling with the BRD4-EP300 CRC to activate intrinsic IIR and cell-state transition genes. Our data suggest that innate training is the consequence of dynamic BRD4 CRC interactions through enhanced EP300 recruitment that primes transcriptional responsiveness.
    Keywords:  H3K27 acetylation; TLR3; innate immune memory; innate immune response; innate training
    DOI:  https://doi.org/10.3389/fimmu.2026.1923234
  10. Nat Aging. 2026 Aug 12.
    Author Correction: Trained immunity links hematopoietic stem cell aging to aging-associated inflammation.
    Wei-Chieh Mu, Marine Barthez, Yufan Feng, Yibing Chen, Chih Ling Wang, Jing-Yi Huang, Jie Li, Paul Lanhart, K Claire Tsuei, Yang Joon Kim, Eric Verdin, Mihai G Netea, Danica Chen.
      
    DOI:  https://doi.org/10.1038/s43587-026-01213-z
  11. J Family Med Prim Care. 2026 Jun;15(6): 2220-2223
    BCG-induced trained immunity on clinical outcomes in moderate to severe COVID-19 patients at a tertiary care center: A comparative study based on interferon-gamma release assays status.
    Akhil Dhanesh Goel, Neetha Thayil Ramankutty, Neha Mantri, Nitesh Kumar, Aditya Kundu, Ravi Shekhar Gadepalli, Ankur Sharma, Manoj Kumar Gupta, Pankaj Bhardwaj, Suman Saurabh, Naveen Dutt, Pradeep Bhatia, Praveen Sharma, M K Garg, Vijay Lakshmi Nag, Sanjeev Misra.
       Background: (BCG) Bacillus Calmette-Guérin-induced trained immunity has enhanced non-specific protection against a range of pathogens, boosting the immune system's ability to respond to infections beyond its primary target, tuberculosis. This study explores the effect of indirect immunity by BCG vaccine as ascertained by interferon-gamma release assays (IGRA) values and clinical outcomes in COVID-19 patients.
    Methods: A purposive sampling of 110 severe and moderate COVID-19 patients admitted to a Tertiary care center, Rajasthan was conducted. QuantiFERON-TB (QFT) tests were applied to measure IGRA levels in the blood sample. Clinical outcomes like the length of hospital stay and in-hospital mortality were studied. Mann-Whitney and Fischer's Exact Tests were used to determine the significance of the association using P-values.
    Results: A total of 13 out of 110 individuals were found to be IGRA positive. The age difference between the two groups was not significant. Most of the patients, who tested negative on the IGRA test were male (90.2%). There was a significant difference in the duration of hospital stay between the two groups (IGRA positive (2-11 days); IGRA negative (7-16 days); and P = 0.049).
    Conclusion: BCG-induced trained immunity shortens the duration of hospital stay in COVID-19 affected individuals. More studies on cross-protection offered by BCG vaccines may help understand the potential role of trained immunity in reducing the severity and spread of other viral infections, including COVID-19. This research could have significant implications for public health strategies and the development of novel vaccination approaches to combat infectious diseases more effectively.
    Keywords:  BCG vaccine; COVID-19; SARS CoV-2; hospital mortality; interferon-gamma release tests; length of stay; tertiary care centers; vaccination coverage
    DOI:  https://doi.org/10.4103/jfmpc.jfmpc_1348_25
  12. Biomed Pharmacother. 2026 Aug 13. pii: S0753-3322(26)00884-X. [Epub ahead of print]203 119848
    Genetic analysis of inflammatory proteins following BCG vaccination in Danish children.
    Collins K Boahen, Thomas N Nissen, Nina M Birk, Mihai G Netea, Christine Stabell Benn, Vinod Kumar.
      The Bacillus Calmette-Guérin (BCG) vaccine, primarily designed for tuberculosis, exerts non-specific immunological effects that vary considerably among children. Limited knowledge exists regarding genetic variants that can impact immune responses post-vaccination. Understanding the genetic factors influencing the immune response in children following BCG vaccination is crucial for optimizing vaccine strategies. Genome-wide pQTL mapping of 65 circulating inflammatory proteins profiled at Month 13 uncovered 11 independent genome-wide significant loci. Following pQTL mapping in BCG-unvaccinated children, whose mean age was not significantly different from that of BCG-vaccinated children, a P-value lookup complemented with statistical colocalization and interaction analyses identified four pQTLs (rs10217747: CXCL11, rs13187850: CD6, rs56283092: LAP-TGF-beta 1, and rs11708321: CDCP1) showing evidence of genotype-by-BCG interactions and larger effect estimates in the BCG group. These variants have previously been associated with inflammatory and autoimmune traits. Genetic analysis of in vitro cytokine production capacity after BCG vaccination identified nominal associations mainly at Month 13 rather than Day 4 or Month 3. These findings enhance our understanding of immune responses to vaccination in children but, given the exploratory genome-wide approach, should be considered hypothesis-generating and require further validation.
    Keywords:  And genetic variation; BCG vaccination; Cytokines; Inflammation; PQTL
    DOI:  https://doi.org/10.1016/j.biopha.2026.119848
  13. EMBO J. 2026 Aug 13.
    Multi-level transcriptional control of specific macrophage responses.
    Alexandra Drakaki, Josje M A Huisman, Marten A Hoeksema.
      Macrophages can adopt diverse functional states in response to environmental cues, a process that is fundamentally controlled at the level of transcriptional regulation. In this review, we outline a hierarchical framework of transcription factor activity that underpins macrophage identity and activation. Firstly, lineage-determining transcription factors establish the cell-type-specific chromatin landscape during development. Upon tissue seeding, local signals shape the activity of additional transcription factors that refine enhancer landscapes and drive tissue-specific macrophage phenotypes. Macrophages further adopt their functional states when exposed to potential threats to tissue homeostasis, such as bacterial ligands or inflammatory cytokines. In response, signal-dependent transcription factors are activated and initiate signal-appropriate transcriptional programs. The specificity and durability of these responses are determined by secondary transcription factors that modulate the magnitude, timing, and maintenance of stimulus-induced transcriptional programs. Collectively, macrophage responses emerge from the activity of interconnected layers of cell-type-, tissue-, and signal-dependent transcription factors, forming complex regulatory networks that inflict stimulus-specific outcomes. Dysregulation of these networks can transcriptionally rewire macrophages toward disease-associated states. Delineating transcriptional regulators that distinguish signal responses may enable more targeted disease interventions.
    DOI:  https://doi.org/10.1038/s44318-026-00898-7
  14. Cell Death Differ. 2026 Aug 08.
    An epigenetic switch in β-cells links mitochondrial stress to inflammatory fate via HMGB1 acetylation.
    Yao Cheng, Luyao Wang, Xue Bai, Guoqi Zhu, Ying Xu, Bin Wang, Qiying Yi, Guangneng Liao, Jinglan Huang, Dan Wang, Sirong He.
      Pancreatic β-cell failure in diabetes is driven by chronic inflammation, yet how metabolic stress determines pro-inflammatory cell fate remains unclear. Here, we report that sublethal oxidative stress activates a β-cell-enriched epigenetic switch that licenses intrinsic inflammation. We identify a β-cell-enriched vulnerability wherein oxidative stress disrupts mitochondrial NAD⁺/acetyl-CoA flux, skewing the nuclear equilibrium between the deacetylase SIRT1 and acetyltransferases p300/CBP. This metabolic-epigenetic imbalance induces hyperacetylation of the alarmin HMGB1 at K96/K128-a modification remarkably prominent in β-cells compared to macrophages or hepatocytes. This site-specific acetylation acts as a molecular gate for HMGB1 nucleocytoplasmic translocation, triggering TLR/RAGE-mediated inflammation. Simultaneously, we discover that oxidative stress co-opts the mechanosensitive Hippo pathway, which sequesters YAP to transcriptionally repress SIRT1, thereby forming a functionally integrated signalling axis that exacerbates HMGB1 acetylation. Therapeutically, reconstruction of mitochondrial retrograde signalling via NAD⁺ supplementation (e.g., NMN) or dual inhibition of mitochondrial ROS and Hippo signalling restored acetylation homeostasis and suppressed HMGB1-driven inflammation. Notably, this combinatorial targeting demonstrates greater efficacy than either intervention alone (~73% reduction in inflammatory markers) in mitigating β-cell failure across murine and porcine models. Further validation in non-human primates was specifically implemented to address the unique translational gap of rodent models and available human single-cell datasets: by leveraging human-like islet anatomy and systemic physiological microenvironment, we verified the pharmacodynamic robustness and in vivo feasibility of this strategy in a clinically recapitulative large-animal setting, rather than merely confirming cross-species molecular concordance. Our work unveils a stress-responsive signalling network in which metabolic and mechanical cues are integrated at the epigenetic level to control the inflammatory fate of β-cells, providing a new mechanistic framework for diabetic pathogenesis and a rationale for combinatorial therapeutic intervention. Oxidative stress triggers mitochondrial dysfunction in pancreatic β-cells, depleting NAD⁺ and accumulating acetyl-CoA. This metabolic crisis skews the SIRT1/p300 balance, inducing β-cell-enriched hyperacetylation of HMGB1 at K96/K128-a molecular switch for its nucleocytoplasmic translocation, which activates TLR/RAGE-mediated intrinsic inflammation. Concurrent Hippo pathway activation further exacerbates this process by repressing SIRT1, forming an integrated signaling axis. To ensure reproducibility, we define a minimal validation workflow using β-TC-6 cells or primary islets under standardized sublethal stress. The central mechanism can be verified by monitoring HMGB1 K96/K128 acetylation and nucleocytoplasmic translocation, while the inflammatory cascade can be effectively blunted through modular rescue approaches, including NAD+ supplementation (NMN), mitochondrial ROS inhibition or hippo pathway inhibition.
    DOI:  https://doi.org/10.1038/s41418-026-01839-x
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