bims-traimu Biomed News
on Trained immunity
Issue of 2026–09–06
fourteen papers selected by
Yantong Wan, Southern Medical University
  1. A konjac glucomannan-based hydrogel delivery system induces trained immunity via enhanced oxidative phosphorylation for improved vaccine protection.
  2. The TRIM-cancer paradox: BCG as a programmable vaccine platform and a mechanistic probe for rational immunotherapy design.
  3. Immunogenic cell death in CNS diseases: From bench to bedside.
  4. In vitro protocols for inducing and assessing endotoxin tolerance in human and murine macrophages.
  5. MAP17 Orchestrates SGLT2-Dependent Glycolytic Reprogramming to Drive Trained Immunity and Accelerate Atherosclerosis.
  6. IBD-related inflammatory memory and colorectal cancer: epigenetic mechanisms and microbiome interventions.
  7. AOAH-mediated LPS inactivation limits macrophage endotoxin tolerance and promotes inflammation and fibrosis in MASH.
  8. Role of DLL4 in Neutrophil Aging and Impaired Clearance in Sepsis.
  9. Immunosuppression in the Pathophysiology of Sepsis.
  10. Cross-tissue single-cell atlas reveals Id2 promotes sepsis-induced tissue damage by mediating macrophage metabolic reprogramming via Pkm2.
  11. Guanine promotes acute lung injury by repressing H3K27me3 in sepsis.
  12. Predicting cellular responses to perturbation across diverse contexts with State.
  13. Itaconate and its derivatives in human health and diseases.
  14. Innate immune sensors of inflammasomes and PANoptosomes: structural-mechanistic insights and therapeutic implications.
  1. Carbohydr Polym. 2026 Oct 15. pii: S0144-8617(26)00801-5. [Epub ahead of print]390 125684
    A konjac glucomannan-based hydrogel delivery system induces trained immunity via enhanced oxidative phosphorylation for improved vaccine protection.
    Zheng Jia, Yadong Gao, Husile Han, Chaonan Wang, Jiaqing Wang, Junjie Guo, Shuhe Zhang, Yifan Li, Junwei Ge, Fang Wang, Mingchun Gao.
      Subunit vaccines represent a leading platform in modern vaccinology due to their defined antigenicity and favorable safety profiles. However, their efficacy requires advanced adjuvants to overcome limited immunogenicity. While plant-derived polysaccharides are widely recognized for their immunostimulatory properties, their capacity to induce trained immunity remains largely unexplored. This study demonstrates, for the first time, that a Konjac glucomannan (KGM)-based hydrogel can induce trained immunity. Specifically, we developed an injectable hydrogel composed of KGM and carboxymethyl cellulose (CMC) that confers protection against Staphylococcus aureus infection via trained immunity. Mechanistically, peritoneal macrophages from KGM/CMC-trained mice exhibited a metabolic shift toward oxidative phosphorylation, accompanied by the significant accumulation of key metabolites such as succinate and palmitate. This KGM/CMC-induced trained immunity provided rapid protection within 3 days and broad-spectrum defense against Gram-positive bacteria. Furthermore, the hydrogel synergized with specific antigens and aluminum adjuvants to significantly potentiate single-dose subunit vaccines, increasing the survival rate of challenged mice to 50%. These findings identify the KGM/CMC as a promising delivery vehicle for vaccines leveraging trained immunity and establish a proof-of-concept for adapting plant-derived bioactive polysaccharides into next-generation immunomodulatory tools.
    Keywords:  Delivery system; Hydrogel; Konjac glucomannan; Trained immunity
    DOI:  https://doi.org/10.1016/j.carbpol.2026.125684
  2. Front Immunol. 2026 ;17 1930908
    The TRIM-cancer paradox: BCG as a programmable vaccine platform and a mechanistic probe for rational immunotherapy design.
    Victor V Pleshkan, Liya G Kondratyeva, Marina V Zinovyeva, Olga A Bezborodova, Irina V Alekseenko, Peter V Shegay, Andrey D Kaprin.
      BCG, a first-generation live vaccine, is being reconsidered as an immunological platform. Interest in its heterologous protection intensified during the pandemic. However, large-scale clinical trials revealed inconsistencies in the efficacy of native BCG. This review argues that BCG's main value lies in its potential as a modifiable vector platform and in its ability to reveal tractable molecular pathways for therapeutic design. This review summarizes the molecular basis of BCG-induced trained immunity (TRIM), focusing on PRR-driven signaling, metabolic rewiring, and epigenetic remodeling in innate immune cells and hematopoietic progenitors. It also maps their convergence with pathways that sustain pro-tumorigenic inflammation. The original conceptual paradigm of the "TRIM-Cancer Paradox" is presented. This paradigm posits that the same innate immune circuits that mediate protective heterologous responses can drive tumor-promoting inflammation and immune escape under conditions of chronic dysregulation. Recombinant BCG (rBCG) is further analyzed as a strategy to rationally amplify or redirect these circuits, the current clinical landscape of BCG-based interventions across various diseases and oncological malignancies is highlighted, and specific molecular nodes that could be exploited to increase the precision, efficacy, and safety of rBCG-based therapies are identified. Overall, this review proposes BCG a programmable immunological platform and to use the TRIM-Cancer Paradox as a novel design principle for next-generation rBCG platforms that transcend traditional vaccinology and cancer immunotherapy applications.
    Keywords:  BCG; bacillus Calmette-Guérin; cancer; heterologous protection; immunotherapy; recombinant BCG; trained immunity; vaccines
    DOI:  https://doi.org/10.3389/fimmu.2026.1930908
  3. Ageing Res Rev. 2026 Aug 29. pii: S1568-1637(26)00334-X. [Epub ahead of print]122 103342
    Immunogenic cell death in CNS diseases: From bench to bedside.
    Pengfei Li, Zilin Zhou, Yongzhi Qing, Xuan Wei, Zhigang Mei, Wenli Zhang.
      The central nervous system (CNS) harbors a distinct immune memory programming system, wherein immunogenic cell death (ICD) acts as a pivotal signaling hub. A spectrum of insults, from systemic metabolic dysfunction to local protein aggregation and ionic dyshomeostasis, can provoke ICD in neurons, glia, and resident immune cells. This process orchestrates the release of damage-associated molecular patterns (DAMPs) from distinct subcellular compartments. These DAMPs synergistically initiate both innate trained immunity (TI), characterized by profound metabolic-epigenetic reprogramming, and antigen-specific adaptive immune responses that traverse the blood-brain barrier. Together, these pathways constitute an integral network of central immune surveillance. Crucially, this ICD-driven immune programming exhibits a striking functional dichotomy depending on the pathological context. In non-neoplastic conditions such as neural injury and neurodegenerative diseases, uncontrolled ICD signaling can establish a pathological trained immune memory, driving a self-perpetuating cycle of chronic neuroinflammation and tissue damage. Conversely, within the tumor microenvironment of malignancies like glioma, the adaptive immune responses elicited by ICD are frequently subverted by potent immunosuppressive mechanisms, culminating in tumor immune escape. This review dissects the differential regulatory mechanisms of ICD-mediated immune memory in CNS tumors versus non-tumor diseases. We aim to elucidate the molecular switches that govern the transition of this immune program from a beneficial, compensatory state to a pathological, detrimental phenotype. By exploring emerging therapeutic strategies, including gene editing, nanomaterials, and bioactive phytochemicals that precisely target ICD pathways, we provide a theoretical framework for understanding CNS immune homeostasis and for the rational design of precision immunotherapies.
    Keywords:  Central nervous system diseases; Damage-associated molecular patterns; Immunogenic cell death; Therapeutic strategies; Trained immunity
    DOI:  https://doi.org/10.1016/j.arr.2026.103342
  4. Methods Cell Biol. 2026 ;pii: S0091-679X(26)00181-0. [Epub ahead of print]210 171-188
    In vitro protocols for inducing and assessing endotoxin tolerance in human and murine macrophages.
    Aoife P Smith, Mathew J Choaji, Emma M Creagh.
      Macrophages are key innate immune effector cells capable of responding to microbial factors such as lipopolysaccharide (LPS) through activation of inflammatory pathways. However, repeated LPS exposure can lead to endotoxin tolerance, a reprogrammed state where macrophages suppress pro-inflammatory cytokine production while preserving antimicrobial functions. The reduction in inflammatory responses during endotoxin tolerance serves to preserve tissue integrity and macrophage viability, although it can also result in immunosuppression, as observed in sepsis. An enhanced understanding of the molecular mechanisms which govern endotoxin tolerance in macrophages could unlock new ways to modulate innate immunity. Here we provide detailed protocols for inducing and measuring tolerance in murine bone marrow-derived macrophages (BMDMs) and human PMA-differentiated THP-1 macrophages, using ELISA-based quantification of IL-1β and IL-6 as functional readouts. These methods provide robust in vitro systems to study endotoxin tolerance.
    Keywords:  Cytokines; Endotoxin tolerance; Enzyme linked immunosorbent assay (ELISA); Lipopolysaccharide (LPS); Macrophages
    DOI:  https://doi.org/10.1016/bs.mcb.2026.05.013
  5. Arterioscler Thromb Vasc Biol. 2026 Sep 03.
    MAP17 Orchestrates SGLT2-Dependent Glycolytic Reprogramming to Drive Trained Immunity and Accelerate Atherosclerosis.
    Jianjin Wu, Lei Wang, Fukang Zou, Fangbing Liu, Guanyu Fang, Kai Cheng, Haochen Gao, Kangkang Zhi, Lefeng Qu.
       BACKGROUND: Atherosclerosis is driven by metabolic-immune crosstalk, in which trained immunity sustains vascular inflammation. MAP17 (membrane-associated protein 17), a redox- and metabolism-regulating adaptor protein, functions as a potential upstream driver of SGLT2 (sodium-glucose cotransporter 2). We aimed to determine whether MAP17 links hyperglycemia to glycolytic activation, inflammatory polarization, and plaque progression in atherosclerosis.
    METHODS: MAP17 expression and its correlations with clinical risk factors were analyzed in serum from 30 patients with atherosclerosis. A trained immunity model was established in bone marrow-derived macrophages via sustained high glucose and IFN-γ (interferon-γ)/lipopolysaccharide stimulation. Functional assays were performed after MAP17 overexpression/knockdown, SGLT2 silencing, or glycolysis inhibition.
    RESULTS: MAP17 was significantly coupregulated in patients with atherosclerosis, with the highest levels observed in those with concomitant diabetes or metabolic syndrome, and closely associated with elevated proinflammatory M1-like cytokines. Immunohistochemistry of carotid plaques confirmed its colocalization with SGLT2 within CD68+ macrophage-rich, lipid-laden, and inflamed regions. In bone marrow-derived macrophages, high glucose robustly induced MAP17 expression, which unidirectionally upregulated SGLT2, enhanced glycolytic flux, increased lactate production, and promoted M1-like polarization and foam cell formation. MAP17 knockdown markedly suppressed SGLT2 expression, glycolysis, and TNF-α (tumor necrosis factor-α)/IL (interleukin)-1β secretion, whereas MAP17 overexpression restored glycolytic activity, proinflammatory phenotype, and foam cell generation even in SGLT2-deficient cells. In diabetic chimeric Apoe-/- mice, MAP17 activation correlated with increased glycolytic marker expression, higher proinflammatory M1-like macrophage ratios, aggravated vascular inflammation, and greater plaque burden; these effects were mitigated by MAP17 or SGLT2 silencing, or by glycolysis inhibition.
    CONCLUSIONS: MAP17 is a key upstream controller of the SGLT2-glycolysis axis that promotes trained immunity and accelerates atherosclerosis. Targeting MAP17 may disrupt the metabolic-inflammatory feedback loop and represents a promising therapeutic strategy for diabetic atherosclerosis.
    Keywords:  atherosclerosis; glycolysis; oxidative stress; reactive oxygen species; trained immunity
    DOI:  https://doi.org/10.1161/ATVBAHA.126.324585
  6. Front Immunol. 2026 ;17 1912351
    IBD-related inflammatory memory and colorectal cancer: epigenetic mechanisms and microbiome interventions.
    Guojun Gao, Xin Zhao, Xingyu Lu, Shuyue Yu, Lihua Chen.
      Colitis-associated cancer (CAC) develops within chronically inflamed mucosa and differs from sporadic colorectal cancer in its field effects, multifocality, and sequence of molecular events. In addition to ongoing inflammation and mutation, experimental studies indicate that epithelial, immune, and stromal compartments can retain altered states after an initiating inflammatory stimulus has subsided. In this review, inflammatory memory is used operationally for a persistent molecular, cellular, tissue, or microbial state that changes the response to a later challenge. This definition distinguishes epithelial epigenetic memory from trained innate immunity, adaptive lymphocyte memory or exhaustion, and chronic signaling that depends on continued stimulation. We synthesize evidence for persistent chromatin accessibility, histone modification, DNA methylation, enhancer activity and three-dimensional organization, epithelial plasticity, immune-stromal circuits, and microbiota-derived metabolites. These responses can support mucosal repair, but repeated activation within a genetically altered field may facilitate clonal expansion and tumor development. We also assess emerging methylation, circulating tumor DNA, stool DNA, single-cell, and spatial biomarkers and grade proposed interventions according to evidence from cell culture, organoids, animal models, human tissues, and clinical studies. Because chromatin- and microbiome-directed interventions remain largely preclinical, selective modulation of pathological persistence-not complete "memory erasure"-is the appropriate translational objective.
    Keywords:  colitis-associated cancer; epigenetic regulation; gut microbiota; immune microenvironment; inflammatory memory; precision prevention
    DOI:  https://doi.org/10.3389/fimmu.2026.1912351
  7. Cell Mol Gastroenterol Hepatol. 2026 Aug 29. pii: S2352-345X(26)00149-9. [Epub ahead of print] 101871
    AOAH-mediated LPS inactivation limits macrophage endotoxin tolerance and promotes inflammation and fibrosis in MASH.
    Hanna Lee, So-Jin Sim, Da-Min Han, Seon-Yeop Kim, Rangyeon Lee, Yujin Jeon, Hyolim Kim, Ji In Park, Jeongho Park, Gwendalyn Randolph, Won-Mook Choi, Hye Won Lee, Yong-Hyun Han.
       BACKGROUND & AIMS: Metabolic dysfunction-associated steatohepatitis (MASH), a chronic liver disease, is characterized by persistent low-grade inflammation, partially driven by gut-derived lipopolysaccharide (LPS). Although repeated LPS exposure can induce endotoxin tolerance in innate immune cells, its role in chronic liver diseases remains unclear. Acyloxyacyl hydrolase (AOAH) is an endogenous enzyme that inactivates LPS, potentially modulating this process. We aimed to investigate how AOAH regulates endotoxin tolerance in Kupffer cells (KCs) and how this affects hepatic inflammation and fibrosis during MASH progression.
    METHODS: AOAH-deficient (AOAH-/-) mice and wild-type controls were subjected to multiple dietary MASH models. Inflammatory responses, fibrosis, and transcriptomic changes in liver tissues and isolated KCs were analyzed. Endotoxin tolerance was modulated through β-glucan administration or LPS preconditioning. LPS bioactivity was assessed using TLR4-reporter cell assays.
    RESULTS: LPS-preconditioned KCs exhibited reduced pro-inflammatory cytokine production and transcriptional suppression of inflammatory pathways, indicating tolerance. Despite slight elevation of plasma LPS levels in MASH, upregulation of hepatic AOAH positively correlated with disease severity, suggesting enhanced LPS inactivation but impaired establishment of tolerance. In contrast, AOAH-deficient KCs displayed reinforced endotoxin tolerance, leading to diminished hepatic inflammation and fibrosis. Reversal of tolerance using β-glucan reactivated inflammatory and fibrogenic responses in AOAH-deficient mice, whereas tolerance induction by low-dose LPS preconditioning mitigated MASH pathology, supporting the protective role of macrophage tolerance in chronic liver injury.
    CONCLUSIONS: Endotoxin tolerance in KCs represents a protective mechanism against chronic liver inflammation and fibrosis. AOAH regulates this state by limiting bioactive LPS, thereby modulating the establishment of endotoxin tolerance and downstream inflammatory and fibrotic responses. Enhancing macrophage tolerance by utilizing LPS may offer a novel therapeutic avenue to control the progression of MASH.
    Keywords:  AOAH; Endotoxin tolerance; Kupffer cell; MASH
    DOI:  https://doi.org/10.1016/j.jcmgh.2026.101871
  8. Inflamm Res. 2026 Sep 03. pii: 194. [Epub ahead of print]75(1):
    Role of DLL4 in Neutrophil Aging and Impaired Clearance in Sepsis.
    Hui Jin, Saoirse Holland, Alok Jha, Monowar Aziz, Ping Wang.
      Sepsis remains a major cause of mortality, largely due to acute lung injury (ALI) driven by excessive neutrophil mediated inflammation. We recently identified a pathogenic subset of DLL4⁺ neutrophils that expands in inflamed lungs and promotes ALI, yet the underlying mechanisms remain unclear. Here, we investigated how DLL4⁺ neutrophils modulate alveolar macrophage (AM) function to exacerbate lung injury. AMs were treated with DLL4⁺ neutrophils or recombinant DLL4 (rmDLL4), and macrophage polarization was assessed by flow cytometry. Conditioned medium was subsequently applied to bone marrow-derived neutrophils (BMDNs) to evaluate neutrophil aging and CD47 expression (don't eat me signal on neutrophils). We showed that DLL4⁺ neutrophils activate the Notch1 signaling pathway in AMs, promoting toward a proinflammatory M1 phenotype. M1 cells markedly upregulate leukotriene B4 (LTB4) production through 5-lipoxygenase activation (5-LOX), inducing the accumulation of aged neutrophils (CXCR4hiCD62Llow). These aged neutrophils markedly increase CD47 expression, leading to impaired macrophage mediated phagocytosis and amplified lung inflammation. Importantly, we developed a novel DLL4-Notch1 inhibitory peptide (NDI) that reprograms AMs toward an anti-inflammatory M2 phenotype, reduces LTB4 release and aged neutrophils, lowers CD47 expression in a murine model of sepsis. Together, we identify DLL4⁺ neutrophils as key orchestrators of macrophage dysregulation in sepsis-induced ALI and demonstrate NDI may represent a potential therapeutic candidate in sepsis-induced ALI.
    Keywords:  Acute lung injury; Alveolar macrophages; DLL4-Notch1 signaling; DLL4⁺ neutrophils; Leukotriene B4; Neutrophil aging; Sepsis
    DOI:  https://doi.org/10.1007/s00011-026-02315-5
  9. Crit Care Clin. 2026 Oct;pii: S0749-0704(26)00039-4. [Epub ahead of print]42(4): 875-889
    Immunosuppression in the Pathophysiology of Sepsis.
    Tristan Couwenbergh, Wouter A van der Heijden, Mihai G Netea.
      Sepsis-induced immunosuppression contributes to mortality, increased susceptibility to secondary infections and long-term complications. Myeloid cells undergo functional reprogramming, while adaptive immune cells, particularly T lymphocytes, show altered composition and lymphopenia. This immunosuppression is driven by several mechanisms. Therapies, including immune-stimulating cytokines, checkpoint inhibitors, and mesenchymal stem cells, are under investigation to restore immune function, but their effectiveness in clinical practice is still unclear.
    Keywords:  Immune dysregulation; Immunotherapy; Sepsis immunosuppression; Sepsis-induced immunoparalysis
    DOI:  https://doi.org/10.1016/j.ccc.2026.05.010
  10. Int J Biol Sci. 2026 ;22(13): 7471-7486
    Cross-tissue single-cell atlas reveals Id2 promotes sepsis-induced tissue damage by mediating macrophage metabolic reprogramming via Pkm2.
    Xiaodan Wang, Yiyan Liu, Yuanqun Zhou, Liyong Zou, Xiaowei Zhou, Zhongyuan Du, Daiqin Bao, Yibo Zhao, Yu Zhu, Yue Wu, Xingnan Ouyang, Li Wang, Liangming Liu, Tao Li.
      As important immune cells, macrophage polarization is directly related to tissue damage in sepsis, and the polarization of macrophages is associated with their metabolic patterns. Previous studies exploring macrophage function in sepsis mainly focused on specific tissues, lacking comprehensive comparisons between tissues. Herein, we performed single-cell RNA sequencing (scRNA-seq) to systematically profile macrophages derived from the brain, heart, intestine, lung, spleen, and peripheral blood mononuclear cells (PBMCs) under homeostatic and septic conditions. Under steady-state, we detected the markers of macrophages in different tissues, classified the macrophages into 10 functional subtypes and compared the differences in their distribution among tissues. In sepsis, we found that Pkm2 and Id2 played important roles in macrophage glycolysis. Mechanistically, Id2 mediated the metabolic reprogramming of macrophages by regulating the chromatin accessibility of Pkm2. Helichrysetin, an inhibitor of Id2, could significantly alleviate tissue damage and increase the survival of septic mice. In summary, our research depicted a cross-tissue macrophage landscape at the single-cell level that encompasses both homeostasis and sepsis. We also provided a new target and a potential drug for the treatment of sepsis by inhibiting macrophage metabolic reprogramming.
    Keywords:  Id2; Pkm2; macrophages; metabolic reprogramming; sepsis
    DOI:  https://doi.org/10.7150/ijbs.136855
  11. Protein Cell. 2026 Sep 03. pii: pwag065. [Epub ahead of print]
    Guanine promotes acute lung injury by repressing H3K27me3 in sepsis.
    Chao-Qun Wang, Hui-Juan Wang, Yue-Yu Kong, Xiayila Abulaiti, Xiao-Hui Zhang, Liu Liu, Rui-Feng Shi, Sheng Hu, Xu Li, Mei-Xin Li, Lu Wang, Jia-Xi Lei, Jing Zhang, Li-Min Xiang, Long-Fei Wang, Tao Long, Hai-Ning Du, Li-Ying Zhan, Wei Yan.
      Sepsis is systemic inflammation with high mortality, accompanied by multi-organ failure including acute respiratory distress syndrome. Extracellular vesicles (EVs) encapsulating bioactive cargoes, mediate cell-cell communication to exert systemic regulation. However, whether and how host lung tissue responds quickly to plasma bacterial infection through EVs in sepsis is poorly understood. Here, we identify that peripheral blood macrophages secrete more exosomal G6PD protein to induce lung injury by rewiring purine metabolism during sepsis. Guanine accumulation reduces H3K27 trimethylation and subsequently induces Nos2, Ccl6 and Il6 expression by suppressing de novo EZH2 synthesis. Macrophage-specific Rab27a or G6pd knockout mice had low exosomal G6PD protein in serum, and failed to exert lung injury upon bacterial infection. Beyond, targeting macrophage-derived G6PD by G6PD inhibitors or engineered EVs delivering si-G6pd relieves lung injury in septic mice. In summary, our findings reveal that circulating G6PD promotes lung injury by rewiring purine metabolism and remodeling the epigenetic profile in sepsis, shedding light on the critical role of EVs as a pro-inflammatory signal and targeting G6PD for future sepsis diagnosis and treatment.
    Keywords:  epigenetic remodeling; extracellular vesicles; lung injury; purine metabolism; sepsis
    DOI:  https://doi.org/10.1093/procel/pwag065
  12. Cell. 2026 Aug 31. pii: S0092-8674(26)00921-9. [Epub ahead of print]
    Predicting cellular responses to perturbation across diverse contexts with State.
    Abhinav K Adduri, Dhruv Gautam, Beatrice Bevilacqua, Mohsen Naghipourfar, Alishba Imran, Rohan Shah, Noam Teyssier, Rishi Verma, Christopher Carpenter, Basak Eraslan, Francis Chalissery, Rajesh Ilango, Vishvak Subramanyam, Chiara Ricci-Tam, Sanjay Nagaraj, Aidan Winters, Mingze Dong, Stefanie Fellinger, Adam Krejci, Tilmann Burckstummer, Sravya Tirukkovular, Jeremy Sullivan, Brian S Plosky, Nicholas D Youngblut, Jure Leskovec, Luke A Gilbert, Silvana Konermann, Patrick D Hsu, Alexander Dobin, Dave P Burke, Hani Goodarzi, Yusuf H Roohani.
      While machine learning models offer potential for predicting transcriptomic effects of perturbation, they currently struggle to generalize across cellular contexts. Here, we introduce State, a machine learning model that predicts perturbation effects while accounting for cellular heterogeneity within and across experiments. State is trained using single-cell gene expression data to predict perturbation effects across sets of cells. State improved discrimination of effects on large datasets by more than 30% and identified differentially expressed genes across genetic, signaling, and chemical perturbations with significantly improved accuracy compared with baselines. Its cell embeddings trained on observational data from 167 million cells enable the identification of strong perturbations in cellular contexts where no perturbations were observed during training. We further introduce Cell-Eval, a comprehensive evaluation framework that can be used to evaluate future models. Overall, the performance and flexibility of State set the stage for scaling the development of AI models of cell state.
    Keywords:  artificial intelligence; cell biology; gene expression; gene regulation; machine learning; perturbation; single-cell RNA sequencing; systems biology; transcriptomics
    DOI:  https://doi.org/10.1016/j.cell.2026.07.052
  13. Signal Transduct Target Ther. 2026 Sep 04. pii: 363. [Epub ahead of print]11(1):
    Itaconate and its derivatives in human health and diseases.
    Jianyou Gu, Wenying Zhang, Junfeng Zhang, Silue Zeng, Renpei Xia, Lei Cai, Xiaosheng Zhong, Shixiang Guo, Huaizhi Wang, Zhe-Sheng Chen.
      Metabolic reprogramming forms the foundation of immune effector functions and the regulation of inflammation. As a pivotal node connecting the tricarboxylic acid cycle to immune signaling, the IRG1/ACOD1 and itaconate axes play a central role in coordinating inflammatory tone and redox balance. Itaconate, generated through the decarboxylation of cis aconitate, acts as an immunometabolic brake that engages multiple regulatory pathways to sustain the dynamic equilibrium between inflammation and tissue homeostasis. Across a broad spectrum of pathological conditions, including infectious diseases, metabolic disorders, ischemia‒reperfusion injury, neurodegenerative diseases, autoimmune disorders, and cancers, itaconate and its derivatives generally exert anti-inflammatory and cytoprotective effects. However, within specific microenvironments, these molecules may also be exploited by pathogens to evade immune clearance or promote immunosuppressive and protumorigenic responses. Future studies should further elucidate tissue- and lineage-specific functions, define bidirectional regulatory mechanisms, and optimize the pharmacokinetic properties of itaconate derivatives. With the advancement of multiomics integration, systems immunology, rational drug design, and engineered itaconate delivery technologies, the IRG1/ACOD1-itaconate axis and derivative-based therapeutic strategies are poised to emerge as key metabolic checkpoints and therapeutic targets in inflammatory-, metabolic-, immune-, and cancer-related diseases.
    DOI:  https://doi.org/10.1038/s41392-026-02936-6
  14. Cell Res. 2026 Sep 04.
    Innate immune sensors of inflammasomes and PANoptosomes: structural-mechanistic insights and therapeutic implications.
    Saurabh Upadhyay, Raghavendra Nagampalli, Sara Resende, Thirumala-Devi Kanneganti.
      Innate immunity provides a critical first line of defense against pathogens and homeostatic perturbations. Pattern recognition receptors detect these disruptions and initiate immune responses through multi-protein complex formation to drive inflammatory signaling and cell death pathways. Key cytosolic complexes formed by these sensors include inflammasomes and PANoptosomes. Inflammasomes induce caspase-1 activation and the subsequent maturation of interleukin (IL)-1β and IL-18, and they can act as integral components of larger PANoptosomes, whose formation and functions have been defined by genetic, biochemical, and single-cell imaging evidence. PANoptosomes induce lytic, inflammatory cell death (PANoptosis) and promote the release of damage-associated molecular patterns (DAMPs) and cytokines beyond IL-1β and IL-18, including TNF, IFNs, IL-6, and others. Given their critical functions in driving cell death and the release of cytokines and DAMPs, dysregulation of innate immune sensors is associated with a wide range of diseases, including infections, autoinflammatory syndromes, cardiovascular disorders, neurodegeneration, metabolic conditions, and cancer. Therefore, understanding innate immune sensors and how they assemble inflammasomes and PANoptosomes to drive cell death is critical for identifying therapeutic strategies. In this review, we discuss innate immune sensors that form inflammasomes and PANoptosomes, such as NLRP1, NLRP3, NLRC4, AIM2, Pyrin, and others. We highlight recent structural and mechanistic insights into these sensors, along with emerging structural studies of inflammasome assemblies and the biochemical and functional evidence supporting the formation of PANoptosomes. Given the physiological relevance of innate immune sensors and the complexes they form across the disease spectrum, an improved understanding of their structure-function relationships will be critical for informing therapeutic strategies that target these molecules, their associated complexes, and their physiological functions.
    DOI:  https://doi.org/10.1038/s41422-026-01287-9
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