bims-traimu Biomed News
on Trained immunity
Issue of 2026–10–25
fifteen papers selected by
Yantong Wan, Southern Medical University
  1. PGRP-SC-mediated innate immune memory against pathogenic bacteria in Drosophila.
  2. Reprogramming innate immune memory in bladder cancer: the proposed bone marrow-bladder axis and next-generation BCG-based immunotherapies.
  3. Histone deacetylase inhibition induces an antitumor IRF8-dependent trained immunity-like status in macrophages.
  4. BCG at 100: The Paradox of an Indispensable Vaccine.
  5. Bioengineering strategies to enhance BCG immunotherapy against bladder cancer.
  6. Adolescent M-CSF Administration Provides Durable Protection Against Trauma-Induced PTSD-Like Phenotypes in Male Mice Through Microglia-Dependent Mechanisms.
  7. Metabolic memory in diabetic complications: evidence for persistent cellular states and limits of therapeutic reversal.
  8. BCG vaccination mitigates tau pathology and restores cognitive function in PS19 mice.
  9. Nanotherapeutic macrophage reprogramming through immunometabolic and microbial modulation for sepsis treatment.
  10. A single-cell atlas of human neutrophils reveals neutrophil heterogeneity across health and disease.
  11. Taurine lowers inflammaging by regulating the NLRP3 inflammasome in macrophages.
  12. NF-κB phosphorylation controls enhancer selection to shape the inflammatory gene program.
  13. Perforin triggers iron-induced mitochondrial damage to drive ferroptosis and anti-tumor immunity.
  14. BEAR-GRN: Systematic assessment of single-cell multi-omics-based gene regulatory network inference methods.
  15. Itaconate protects the blood-brain barrier by preserving microvascular bioenergetics after traumatic brain injury.
  1. Hlife. 2026 Jan;4(1): 41-55
    PGRP-SC-mediated innate immune memory against pathogenic bacteria in Drosophila.
    Zihao Deng, Jiazhen Luo, Yufu Zhang, Chen Li, Shixin Deng, Jiazhi He, Zihao He, Wenqi Wu, Renjie Jiao, Jiyong Liu.
      Trained immunity is essential for innate immune cells to retain a memory of previously encountered pathogens, strengthening the hosts' response against these pathogens. However, the mechanisms governing trained immunity have not been well elucidated. In this study, flies of different genotypes were trained with heat-killed gram-negative (G-) bacteria and subsequently reinfected with live pathogens. The innate immune responses against reinfection were evaluated through assessments of survival rates, antimicrobial peptide expression levels, and bacterial loads, complemented by transcriptomic and chromatin immunoprecipitation (ChIP) analyses. We found that flies trained with heat-killed gram-negative bacteria exhibited a higher survival rate upon secondary infection compared to unprimed flies, which was associated with increased expression of antimicrobial peptides. Priming with G- bacteria increased the sensitivity of the immune deficiency pathway to a second bacterial infection owing to lower levels of peptidoglycan recognition protein SC (PGRP-SC) after the first infection. The gut was the major tissue involved in the downregulation of PGRP-SC expression. The histone H3 lysine 9 trimethylation (H3K9me3) levels were higher at the PGRP-SC loci in immune-trained flies compared to untrained flies, contributing to the suppression of PGRP-SC expression. PGRP-SC overexpression in the fly gut abolished the effect of trained immunity. Taken together, our studies identify an innate immune memory in Drosophila that is regulated by gut-derived PGRP-SC through H3K9me3-mediated epigenetic repression of the PGRP-SC.
    Keywords:  Drosophila melanogaster; gut; histone H3 lysine 9 trimethylation (H3K9me3); innate immune memory; peptidoglycan recognition protein SC (PGRP-SC); trained immunity
    DOI:  https://doi.org/10.1016/j.hlife.2025.09.003
  2. Front Immunol. 2026 ;17 1945559
    Reprogramming innate immune memory in bladder cancer: the proposed bone marrow-bladder axis and next-generation BCG-based immunotherapies.
    Meng Yang, Yu Guo, Yu-Zhao Shen, Yan-Li Sun, Dai-Ju Ma, Yuan-Jia Tang.
      Intravesical Bacillus Calmette-Guérin (BCG) remains the standard adjuvant treatment for high-risk non-muscle-invasive bladder cancer (NMIBC), yet the mechanisms underlying its durable clinical benefit and treatment resistance remain incompletely understood. Although BCG has traditionally been regarded as a local immunotherapy, emerging clinical and preclinical evidence suggests that intravesical BCG can induce trained-immunity-associated systemic immune changes, including alterations in circulating innate immune responses and hematopoietic programming. In this Review, we propose the bone marrow-bladder axis as a hypothesis-generating conceptual framework linking local microbial sensing with systemic hematopoietic responses that may contribute to sustained myeloid and adaptive antitumor immunity. Building upon this framework, we further introduce the Failure-to-Train (FTT) model, which proposes that selected immune-training-related mechanisms may contribute to heterogeneous patterns of BCG failure through disruption of productive immune training at distinct stages of the proposed immune-training circuit. Finally, we discuss the implications of this framework for biomarker development, experimental validation and mechanism-guided immunotherapy. By considering systemic immune training as a potential contributor to BCG responses, this Review provides a conceptual framework for investigating treatment response and resistance and for developing testable strategies for next-generation immunotherapy.
    Keywords:  BCG immunotherapy; BCG resistance; bladder cancer; precision immunotherapy; trained immunity
    DOI:  https://doi.org/10.3389/fimmu.2026.1945559
  3. Nat Commun. 2026 09 22. pii: 11027. [Epub ahead of print]17(1):
    Histone deacetylase inhibition induces an antitumor IRF8-dependent trained immunity-like status in macrophages.
    Xueting Qin, Meida Xiang, Yaqing Guo, Yixin Chang, Zilong Zhang, Jiejie Liu, Xin Zhang, Yuting Pan, Hebing Chen, Weidong Han, Jing Nie.
      Epigenetic reprogramming underlies innate immune memory. However, whether trained immunity can be induced via epigenetic intervention to combat tumors, and the key regulators controlling this process, remain unclear. Here, we demonstrate that histone deacetylase inhibitor (HDACi) priming establishes a trained immunity-like state in monocytes/macrophages, conferring potent antitumor effect in multiple models of triple-negative breast cancer (TNBC) in female mice. Interferon regulatory factor 8 (IRF8) is identified as the master regulator of the inflammatory transcriptional program, which is governed by IRF8-associated super-enhancers and reinforced by HDACi. Myeloid-specific IRF8 deficiency impairs pro-inflammatory macrophage differentiation and abrogates HDACi-induced antitumor efficacy. Moreover, an IRF8-driven, CCL8-expressing macrophage subset recruits and activates cytotoxic CCR5+CD8+ T cells in the TNBC microenvironment. As a proof-of-principle with translational relevance, CCL8-overexpressing EGFR-targeted CAR T cells exhibit enhanced trafficking and improved efficacy in a humanized TNBC model. Our study defines the IRF8-CCL8-CCR5 axis as an epigenetically potentiated nexus of innate and adaptive antitumor immunity.
    DOI:  https://doi.org/10.1038/s41467-026-77904-3
  4. Indian Pediatr. 2026 Oct 22.
    BCG at 100: The Paradox of an Indispensable Vaccine.
    Vipin M Vashishtha.
      Bacille Calmette-Guerin (BCG) vaccine, in use for over a century, occupies a paradoxical position in global health. It protects infants against disseminated tuberculosis (TB) with 60-80% efficacy and reduces all-cause infant mortality through non-specific effects mediated by trained immunity. Yet it provides limited and variable protection against pulmonary TB in adolescents and adults who drive transmission. A tuberculin survey from western Uttar Pradesh documented an annual risk of TB infection of 3.5-4.1%, nearly 50 times the national target, in a predominantly BCG-vaccinated child population. This perspective addresses four fundamental questions: Has BCG become redundant for its original purpose? Can it be improved? Is it more efficacious for non-TB indications? And is it currently indispensable? The pipeline is reviewed from a pediatric prism, identifying preferred candidates for each age group. MTBVAC leads as the most promising infant BCG replacement candidate while M72/AS01E is a frontrunner for adolescents and adults.
    Keywords:  M72/AS01E; MTBVAC; Non-specific effects; Trained immunity; Tuberculosis; VPM1002
    DOI:  https://doi.org/10.1007/s13312-026-00433-1
  5. Front Immunol. 2026 ;17 1888889
    Bioengineering strategies to enhance BCG immunotherapy against bladder cancer.
    Senhao Li, Haige Chen, Bing Feng.
      Bacillus Calmette-Guérin (BCG) remains the frontline immunotherapy for non-muscle-invasive bladder cancer (NMIBC), yet recurrence and non-response occur in over half of patients, highlighting the need for improved therapeutic strategies. Recent advances in bioengineering including genetic modification, synthetic biology, biomaterials, and delivery systems are expanding BCG from a traditional vaccine into a more versatile immunotherapeutic platform. In this review, we summarize the mechanisms of BCG-induced antitumor immunity and discuss current bioengineering strategies aimed at enhancing tumor interaction, innate immune activation, and modulation of the tumor immune microenvironment (TIME). We further highlight emerging approaches in delivery system design to improve intravesical retention and therapeutic efficacy. In addition, we discuss evolving perspectives on immune regulation in BCG therapy, including the potential contribution of type 2 immunity alongside canonical type 1 responses, as well as the role of trained immunity in sustaining antitumor effects. Finally, we outline key challenges for clinical translation and future directions toward more rational and precise BCG-based immunotherapy.
    Keywords:  BCG; bioengineering; bladder cancer; drug delivery; immunotherapy
    DOI:  https://doi.org/10.3389/fimmu.2026.1888889
  6. Neurochem Res. 2026 Oct 20. pii: 301. [Epub ahead of print]51(6):
    Adolescent M-CSF Administration Provides Durable Protection Against Trauma-Induced PTSD-Like Phenotypes in Male Mice Through Microglia-Dependent Mechanisms.
    Fu Li, Minxiu Ye, Lijuan Tong, Chao Huang, Xing Xu, Jie Peng.
      Post-traumatic stress disorder (PTSD) is a severe psychiatric condition for which effective preventive strategies are lacking. Innate immune preconditioning has shown promise for the prevention of PTSD, yet the transient nature of such protection when induced in adulthood poses a substantial limitation. Using male C57BL/6J mice, we tested whether administration of macrophage colony-stimulating factor (M-CSF, 100 µg/kg, intraperitoneally) during adolescence, a developmental period characterized by heightened microglial plasticity, could establish enduring resilience against trauma-induced PTSD-like behaviors. Mice received a single M-CSF injection at postnatal day 28 (PND28) and were subsequently subjected to single prolonged stress (SPS/FS) at 4, 16, or 32 weeks thereafter, with behavioral and molecular assessments conducted at PND70, PND154, and PND266, respectively. Our results showed that adolescent M-CSF exposure substantially prevented SPS/FS-induced anxiety-like behaviors assessed by the elevated plus maze and open field test, and SPS/FS-induced fear-like behaviors evaluated by contextual and cued fear conditioning tests, at all three post-administration intervals. Concurrently, M-CSF pretreatment prevented SPS/FS-induced interleukin-1β (Il-1β), Il-6, and tumor necrosis factor-α (Tnf-α) mRNA expression within the hippocampus and medial prefrontal cortex across all time points examined. These protective phenotypes were eliminated when microglial function was pharmacologically inhibited or when microglia were depleted before M-CSF administration, establishing that microglial integrity at the time of adolescent immune challenge is required for the establishment of long-term resilience. Taken together, these findings demonstrate that a single developmental immune intervention confers lifelong protection against SPS/FS-induced PTSD-like behaviors through microglia-dependent mechanisms, introducing a vaccine-like paradigm for the prevention of PTSD.
    Keywords:  Adolescent microglia; Innate immune memory; M-CSF; Neuroinflammation; PTSD prevention; Stress resilience
    DOI:  https://doi.org/10.1007/s11064-026-04915-3
  7. Front Endocrinol (Lausanne). 2026 ;17 1954392
    Metabolic memory in diabetic complications: evidence for persistent cellular states and limits of therapeutic reversal.
    Yulan Cai, Shuangyu He, Feng Zeng, Chuyu Liu.
      Metabolic memory is defined here as an exposure-history-dependent cellular phenotype that persists beyond immediate carry-over after verified withdrawal of the initiating exposure, principally high glucose and is accompanied by a specified functional impairment or an altered response to the same defined secondary stimulus. This operational definition separates cellular memory from clinical legacy effects, continuing local stimulation and residual structural injury. We critically examine evidence from longitudinal clinical studies, human biospecimens, animal models and controlled cell experiments, distinguishing molecular persistence, measured signaling activity, causal maintenance and treatment-free durability. DCCT/EDIC and UKPDS establish lasting benefits of earlier glycemic management but do not independently identify cellular memory as the mechanism. Experimental evidence supports selected endothelial redox circuits, epigenetic regulation and hematopoietic progenitor training; human causal evidence is substantially more limited. Persistent chromatin marks do not necessarily imply continuously active signaling, and latent priming may become apparent only after rechallenge. In kidney, cardiovascular, retinal and wound disease, candidate cellular memory coexists with hypoxic or inflammatory niches and structural loss. Pancreatic β-cell plasticity is considered a comparative endocrine model rather than an established complication-memory circuit. The proposed interactions among epigenetic, mitochondrial, metabolic and inflammatory mechanisms remain a framework supported by selected local feedback loops, not a universally demonstrated network. Therapeutic evidence is organized into prevention, modification or suppression of established abnormalities, and sustained molecular and functional recovery after treatment cessation after intervention withdrawal. The latter remains unestablished in patients for the mechanisms reviewed. Early glycemic and multifactorial management remains essential, while mechanistic translation requires explicit recovery, perturbation and post-treatment follow-up designs.
    Keywords:  cellular senescence; diabetic complications; epigenetics; immunometabolism; metabolic memory; mitochondrial dysfunction; tissue repair; trained immunity
    DOI:  https://doi.org/10.3389/fendo.2026.1954392
  8. Sci Adv. 2026 Oct 23. 12(43): eaej4603
    BCG vaccination mitigates tau pathology and restores cognitive function in PS19 mice.
    Somnath Shee, Meixiang Huang, Meghraj Singh Baghel, Yuxin Zheng, Shichun Lun, Santosh K Yadav, Nirbhay N Yadav, Carlos E Ruiz-Gonzalez, Sandeep Tyagi, Eric Nuermberger, Sanjay K Jain, Zaver M Bhujwalla, Barbara S Slusher, Philip C Wong, William Bishai.
      Retrospective studies in patients with nonmuscle invasive bladder cancer have reported a significant reduction in Alzheimer's disease incidence (12 to 78%) among Bacille Calmette-Guérin (BCG) recipients versus controls. To investigate the underlying mechanisms, we evaluated BCG in the PS19 mouse model of tauopathy. We found that BCG administration reduced hippocampal phospho-tau and microgliosis while preserving neuronal markers. In vivo volumetric T2-magnetic resonance Imaging (MRI) demonstrated attenuation of brain atrophy accompanied by increased glutamate-weighted chemical exchange saturation transfer-MRI signals. Functionally, BCG-treated mice showed improved performance in the novel object recognition test, as well as improved body-weight maintenance and survival. Transcriptomic profiling of the hippocampus revealed near complete normalization of the PS19 disease-associated gene expression signature toward that of healthy controls. Flow cytometric profiling of brain myeloid populations demonstrated a reduction in activated resident microglia, but total microglia cells remain elevated. Moreover, an increase of trained immunity marker CD80 on the recruited peripheral myeloid cells ensues following BCG treatment. Consistent with this shift in myeloid state, primary brain myeloid cells from BCG-treated mice also exhibited enhanced phagocytosis of fluorescein isothiocyanate-labeled tau fibrils and increased lactate production. Together, these findings indicate that BCG induces systemic and central nervous system myeloid cell reprogramming that limits neuroinflammation, enhances tau clearance, and rescues cognitive and neurodegenerative phenotypes in a tauopathy model. BCG is a safe, readily available therapy that merits consideration as a preventive agent against dementia.
    DOI:  https://doi.org/10.1126/sciadv.aej4603
  9. Signal Transduct Target Ther. 2026 Oct 21. pii: 467. [Epub ahead of print]11(1):
    Nanotherapeutic macrophage reprogramming through immunometabolic and microbial modulation for sepsis treatment.
    Xintong Lu, Wenhui Wang, Bingjie Zhang, Qian Li, Ye Chen, Yongrui Hai, Renming Fan, Shuo Fu, Jiaxin Yan, Guiquan Ding, Zhuang Hou, Junke Song, Maosheng Cheng, Gaofei Wei.
      Sepsis is a life-threatening syndrome characterized by dysregulated immune responses and metabolic dysfunction, and remains a major cause of global mortality. While nanomedicine offers new opportunities for sepsis therapy, current strategies rarely achieve comprehensive modulation of macrophage immunometabolism and microenvironmental signaling. Here, we develop a glutathione-responsive nanotherapeutic platform (EONPs) by conjugating the stimulator of interferon genes (STING) inhibitor 4-octyl itaconate to polyethylene glycol, followed by encapsulation of the dihydroorotate dehydrogenase (DHODH) inhibitor EA6. Integrated transcriptomic, metabolomic, and metagenomic analyses combined with pharmacological assessments reveal that EONPs suppress systemic hyperinflammation, reprogram macrophages toward an anti-inflammatory phenotype, restore gut microbial homeostasis, and protect against multi-organ injury in septic models. Notably, EONPs enhance the production of the microbiota-derived metabolite 5-hydroxyindoleacetic acid (5-HIAA), which is functionally linked to the anti-inflammatory response and may further support macrophage reprogramming. Our findings establish a previously unrecognized strategy for precise metabolic and microbiota-driven modulation of macrophages, offering a conceptual framework for further investigation of macrophage-targeted nanotherapeutics in sepsis.
    DOI:  https://doi.org/10.1038/s41392-026-02947-3
  10. Nat Immunol. 2026 Oct 21.
    A single-cell atlas of human neutrophils reveals neutrophil heterogeneity across health and disease.
    Hong Zheng, Evan Maestri, Andrew R Moore, Ananthakrishnan Ganesan, Jeanna Enriquez, Verónica Durán, Shirit Einav, Tom van der Poll, Hjalmar R Bouma, Mihir R Atreya, Philip A Efron, Lyle L Moldawer, Jonathan Sevransky, David W Wright, Ignacio Martin-Loeches, Thomas Karvunidis, Jeremiah Hinson, David N Hager, Richard E Rothman, Evangelos J Giamarellos-Bourboulis, Timothy E Sweeney, Angela J Rogers, Saurabh Gombar, Manoj V Maddali, Jonathan H Chen, Nigam Shah, Purvesh Khatri.
      Neutrophils, the most abundant leukocytes in human blood, have multifaceted roles in health and disease. Here we assembled a single-cell atlas of human neutrophils (SCAHN) by integrating transcriptome data from 1 million human neutrophils from 781 samples and 43 independent datasets. Using SCAHN, we identified multiple neutrophil subsets with distinct functions across tissues and robust changes in gene expression and subset proportions in infection, cancer, immune suppression and sex differences at single-cell resolution. Cross-species reference mapping of mouse and nonhuman primate neutrophils onto SCAHN revealed both conserved and species-specific features. Using 17,023 bulk blood transcriptome profiles from 40 datasets, we found that neutrophil-specific signatures predicted mortality in acutely ill patients at presentation, were associated with cancer diagnosis and survival, and correlated with metabolic dysfunction and long-term all-cause mortality. Our study highlights how neutrophil biology can improve immune risk stratification and develop effective diagnostic and therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41590-026-02671-8
  11. Cell. 2026 Oct 23. pii: S0092-8674(26)01207-9. [Epub ahead of print]
    Taurine lowers inflammaging by regulating the NLRP3 inflammasome in macrophages.
    Chenyang Guan, Seungjin Ryu, Mingze Dong, Yitao Zhu, Rae Maeda, Yun-Hee Youm, Subhasis Mohanty, Hee-Hoon Kim, Lucie Orliaguet, Tamara Dlugos, Steven R Smith, Eric Ravussin, Janset Onyuru, Hal M Hoffman, Stephan Siebel, Andrew Wang, Yaqiu Wang, Yuval Kluger, Albert C Shaw, Thirumala-Devi Kanneganti, Nathan LeBrasseur, Yuki Sugiura, Vishwa Deep Dixit.
      Whether a decline in taurine drives aging is debated, and despite high millimolar intracellular concentrations, its function as a potential guardian of cytosolic homeostasis is unclear. Here, we show that aging increases circulating taurine concentrations in humans and mice. Further elevating taurine in aged mice enhances health span, engaging anti-inflammatory pathways previously linked to youthfulness, and reduces mortality from sepsis and inflammasome-mediated inflammation, suggesting an enantiostatic response. Mechanistically, diverse NLRP3-specific "danger signals" induce taurine efflux from macrophages as a proximal step to activate the inflammasome and the resultant pyroptosis. Taurine restoration in macrophages prevents NLRP3-induced trans-Golgi network disassembly, thereby suppressing NLRP3 inflammasome activation. Conversely, lowering taurine biosynthesis combined with reduced bioavailability in macrophages exacerbated inflammasome activation. In humans, sustained caloric restriction elevates adipose tissue taurine and is accompanied by lower inflammation. Together, we identify taurine as an immunometabolic rheostat that links danger sensing to NLRP3 inflammasome activation, suggesting taurine-based strategies to alleviate inflammaging and inflammasomopathies.
    Keywords:  NLRP3; aging; antiinflammation; caloric restriction; immunometabolism; inflammaging; inflammasome; lifespan; taurine; taurine efflux
    DOI:  https://doi.org/10.1016/j.cell.2026.09.061
  12. Immunity. 2026 Oct 23. pii: S1074-7613(26)00400-0. [Epub ahead of print]
    NF-κB phosphorylation controls enhancer selection to shape the inflammatory gene program.
    Felipe Batista Leão, Dev Bhatt, Lauren Vaughn, Will Liao, Dillon Maloney, Vincent Guichard, Brea Hampton, Alexander Yang, Thomas S Postler, Ruxiao Yang-Fischer, Jingyao Zhao, Donna Farber, Sankar Ghosh.
      Inflammatory transcriptional responses mediated by NF-κB are diverse despite similar upstream activation signals. Because phosphorylation of the NF-κB subunit RelA/p65 promotes interaction with co-activators CREB-binding protein/E1A binding protein p300 (CBP/p300) and selectively affects gene expression, we asked whether this modification distinguishes regulatory architectures underlying distinct immune functions. In macrophages carrying a Rela Ser276Ala mutation, p65 phosphorylation at serine 276 (S276) was dispensable for NF-κB binding to primed enhancers but essential for recruitment to nucleosome-occluded regions lacking pre-bound transcription factors (TFs) and activating histone marks. Such latent enhancers required phosphorylated NF-κB to recruit CBP/p300, promote histone acetylation, and open chromatin. Genes linked to these enhancers, including inflammatory mediators, were selectively impaired in S276A macrophages. Although antiviral responses remained intact, Rela Ser276Ala mice resisted endotoxin shock but were susceptible to bacterial infection. Thus, NF-κB responses are functionally partitioned by enhancer architecture: phosphorylation-sensitive sites define a latent enhancer compartment with NF-κB-dominated regulatory architecture, whereas primed sites are embedded in broader networks of lineage-determining and inducible TFs, yielding distinct biological outputs.
    Keywords:  CBP/p300; NF-κB; RelA/p65 Ser276 phosphorylation; chromatin remodeling; epigenetic regulation; gene regulation; inflammatory responses; latent enhancers; macrophage activation; post-translational modifications
    DOI:  https://doi.org/10.1016/j.immuni.2026.09.025
  13. Cell. 2026 Oct 23. pii: S0092-8674(26)01208-0. [Epub ahead of print]
    Perforin triggers iron-induced mitochondrial damage to drive ferroptosis and anti-tumor immunity.
    Hannah N Bell, Kavya Nair, Kole Tison, Peng Liao, Hongwei Lei, Marwa O El-Derany, Ayijiang Yisimayi, Haiwei Zhang, Ryan Rebernick, Weichao Wang, Yoshitaka Adachi, Cristina Castillo, Nupur K Das, Jinsu An, Vivien R Sutton, Xun Lin, Heng Lin, Xinghao Wang, Yunfei Li, Linda Vatan, Amr Aboud, Shuang Wei, Miguel Gijon, Samantha Goodwin, Yatrik M Shah, Ilona Kryczek, Joseph A Trapani, Margarida Barroso, Judy Lieberman, Weiping Zou.
      Cytotoxic CD8+ T cells and natural killer cells are critical effectors of anti-tumor immunity. Cytotoxic lymphocytes eliminate tumor cells by releasing perforin (Prf1), a pore-forming protein that enables granzymes (Gzms) to enter target cells and trigger both caspase-dependent and -independent cell death. Here, we uncover a previously unrecognized, Gzm-independent function of Prf1. We find that Prf1 directly induces tumoral ferroptosis, an iron- and lipid-dependent form of cell death. Mechanistically, Prf1-mediated pore formation drives endocytosis of the transferrin receptor, which increases cellular iron uptake. Prf1 promotes the formation of endosomal-mitochondrial contacts, which leads to mitochondrial iron accumulation, mitochondrial dysfunction, and tumor cell ferroptosis. Dietary iron supplementation suppresses tumor progression in murine tumor models in a Prf1-dependent manner. Higher Prf1 expression correlates with improved survival and enhanced response to immune checkpoint blockade in patients with cancer. These findings define a Gzm-independent function of Prf1 as a direct executioner of cancer cell death through ferroptosis.
    Keywords:  NK cell; T cell; ferroptosis; granzyme; immune checkpoint blockade; iron; mitochondria; perforin
    DOI:  https://doi.org/10.1016/j.cell.2026.09.062
  14. Nat Commun. 2026 09 18. pii: 10971. [Epub ahead of print]17(1):
    BEAR-GRN: Systematic assessment of single-cell multi-omics-based gene regulatory network inference methods.
    Karamveer Karamveer, Eric Moeller, Hannah Valensi, Ewura-Esi Manful, Yasin Uzun.
      Identifying regulatory gene interactions is inherently challenging as it depends on both the transcriptional and epigenetic landscapes. Multiple methods are proposed to infer gene regulatory networks (GRNs) using single-cell multi-omics data, yet the absence of a standardized benchmarking framework remains an obstacle to unbiased performance evaluation. Here we present BEAR-GRN, a systematic resource providing standardized datasets, curated ground-truth networks, and a unified computational pipeline for benchmarking GRN inference methods. Using BEAR-GRN, we assess state-of-the-art multi-omics GRN inference methods across paired single-cell RNA-seq and ATAC-seq datasets spanning human and mouse cell types. We evaluate accuracy against four complementary ground-truth definitions, alongside computational efficiency, output stability, and modality contribution. Although ground-truth choice profoundly influences performance, LINGER and DIRECT-NET show the highest overall accuracy and stability. Modality perturbation experiments reveal that current methods are predominantly RNA-driven, with chromatin accessibility contributing limited independent signal. BEAR-GRN enables researchers to evaluate existing and new GRN methods against established baselines.
    DOI:  https://doi.org/10.1038/s41467-026-77838-w
  15. Redox Biol. 2026 Oct 20. pii: S2213-2317(26)00445-3. [Epub ahead of print]98 104446
    Itaconate protects the blood-brain barrier by preserving microvascular bioenergetics after traumatic brain injury.
    Ning Liu, Di Zhou, Mengxuan Shi, Yuwen Xiu, Yinghua Jiang, Yingjie Wang, Gaby A Moyano, Jack L McGuire, Amin Iskender, Mitchell D Kilgore, Lixiang Chen, Charles Vidoudez, Yadan Li, Thin Yadanar Sein, Jia Fan, Prasad V G Katakam, Aaron S Dumont, Xiaoying Wang.
      Traumatic brain injury (TBI) is a leading cause of mortality and long-term disability, yet effective pharmacological therapies remain unavailable. Early blood-brain barrier (BBB) disruption accelerates neuroinflammation and secondary brain injury. It has been well recognized that brain microvascular endothelial cells (BMECs) depend on mitochondrial oxidative metabolism to maintain BBB integrity. Here, we investigated the role of the mitochondria-derived immunometabolite itaconate in regulating cerebrovascular bioenergetics and BBB integrity after TBI. Using a controlled cortical impact model, we found that TBI induced early Irg1 upregulation but paradoxically reduced fatty acid-derived itaconate levels in brain microvessels (MVs). TBI also created a hypoxic microenvironment that disrupted the Irg1/itaconate axis in BMECs. Genetic Irg1 deficiency exacerbated microvascular metabolic dysfunction, particularly deficits in fatty acid oxidation (FAO), and BBB breakdown, whereas treatment with 4-octyl itaconate (4-OI) restored mitochondrial metabolism/bioenergetics in brain MVs within 12 h after injury and preserved BBB integrity. Mechanistically, TBI and hypoxia suppressed carnitine palmitoyltransferase 1A (CPT1a), whereas 4-OI restored CPT1a expression, enhanced FAO, and activated Nrf2 signaling, thereby preserving tight junction proteins and VE-cadherin in hypoxia-exposed human BMECs. Together, these findings identify itaconate as a critical regulator of endothelial mitochondrial metabolism and BBB integrity following TBI and support therapeutic targeting of the Irg1/itaconate pathway to prevent secondary neurovascular injury.
    Keywords:  Bioenergetics; Blood-brain barrier; Brain microvessels; Endothelial function; Fatty acid oxidation; Traumatic brain injury
    DOI:  https://doi.org/10.1016/j.redox.2026.104446
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