bims-traimu 2026-10-11 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2026–10–11
fourteen papers selected by
Yantong Wan, Southern Medical University

Maturation-Dependent Constraints in the Ability of Human Monocytes to Initiate Trained Immunity.
Therapeutic targeting of trained immunity in cancer.
Epigenetic reprogramming by BCG (Bacillus Calmette-Guérin) vaccination: A novel strategy to reverse immunodeficiency in chronic kidney disease.
Trained immunity-based mucosal immunotherapies for preventing respiratory infections: a translational, evidence-graded appraisal of platforms, populations, and the protection-immunopathology balance.
Gut-brain immune dysregulation in Parkinson's disease: a hypothesis-forming narrative review of trained immunity.
Inhibiting trained immunity in Duchenne muscular dystrophy enhances muscle regeneration and reduces fat deposition.
Metabolic-epigenetic imprinting of macrophages in endometriosis: a working model for lesion persistence and treatment.
Source-specific priming of lung NK cells by Pseudomonas LPS enhances resistance to bacterial pneumonia.
Transcriptional regulation and function of GPR18 in macrophage subtype specification.
Lactobacillus gasseri suppresses methionine-driven epigenetic programming of trained immunity-like priming to attenuate metabolic dysfunction.
The H3K27me3-NR1D1-IFN-γ axis in trained macrophages induced by early respiratory virus infection drives non-T2 asthma in children.
Histone lactylation scarring transmits metabolic and epigenetic memory across the gut-liver axis.
A non-canonical function of glutathione to suppress ferroptosis via FSP1.
Metabolic reprogramming of pathogenic CD4+ T helper cells attenuates inflammatory bowel disease in mice.

MedComm (2020). 2026 Oct;7(10): e70939

Maturation-Dependent Constraints in the Ability of Human Monocytes to Initiate Trained Immunity.

Michael Eigenschink, Elsa Davogg, Manuel Pristner, David Seki, Marcus Arzmüller, Herbert Kiss, Alex Farr, Angelika Berger, David Berry, Benedikt Warth, Lukas Wisgrill.

  The survival of nonvertebrate species that lack adaptive immunity has prompted the discovery of memory mechanisms in innate immune cells, termed trained immunity. Because infants depend on innate immunity to fight off pathogens, leveraging these mechanisms in neonatal care may hold clinical significance. Yet, this is constrained by limited understanding of innate immune memory development during early-life. By performing systems-level characterization of β-glucan-trained monocytes from adults, term infants, and preterm infants, we report maturation-dependent constraints in trained immunity. We corroborate these findings in a small cohort of premature infants with in utero pathogen exposure. Alongside limited stimulus-induced reprogramming of innate immune responses in the clinical cohort, monocytes from premature infants exhibited metabolic alterations in glutaminolysis and tricarboxylic acid cycle metabolism, pathways central to trained immunity. They also displayed a treatment-robust long noncoding RNA landscape and transcriptional alterations in enzymes relevant to epigenetic induction of innate immune memory. Finally, network-based analyses implicated SMAD5 and ARNT as potential drivers of differences and provided evidence for altered transcriptional regulation of chromatin organization across early-life development. Our results suggest that metabolic and transcriptomic immaturity constrains trained immunity in premature infants, highlighting a developmental mechanism that may affect host defense and guide future immunomodulatory strategies.

Keywords:  infant; metabolomics; monocytes; premature; trained immunity

DOI:  https://doi.org/10.1002/mco2.70939
Curr Opin Pharmacol. 2026 Sep 17. pii: S1471-4892(26)00073-1. [Epub ahead of print]91 102677

Therapeutic targeting of trained immunity in cancer.

Bhumika Deb, Khushal Khambhati, Rakesh Rawal, Ankit Rai, Vijai Singh.

Cancer immunotherapy has transformed the treatment of several malignancies. Yet, its therapeutic efficiency remains ineffective due to the diversity and immune-resistance of the tumor microenvironment (TME). Trained immunity is the capability of innate immune cells to acquire immunological memory upon exposure to specific stimuli, followed by metabolic and epigenetic reprogramming, and offers an emerging strategy against cancers. In various forms of cancer, trained immunity (TI) leads to enhance the cytokine release, reactive oxygen species (ROS) production, phagocytosis, antigen presentation, and modification of the tumor microenvironment, which may have antitumor effects, depending on the tumor type. Mechanistically, the trained immunity is supported by mTOR/HIF1α-mediated aerobic glycolysis, histone modifications of proinflammatory genes, and reprogramming of hematopoietic stem cells and progenitor cells (HSPCs) in the bone marrow, thus driving the central, peripheral, and effector arms of anti-tumor immunity, simultaneously. This review discusses the mechanisms of trained immunity in cancer therapy and evaluates the current therapeutic approaches.

DOI: https://doi.org/10.1016/j.coph.2026.102677
Indian J Med Res. 2026 Aug;pii: 10.25259/IJMR_131_2026. [Epub ahead of print]164(4): 511-521

Epigenetic reprogramming by BCG (Bacillus Calmette-Guérin) vaccination: A novel strategy to reverse immunodeficiency in chronic kidney disease.

Rohit Sharma, Krishna Tiwari, Muhammad Aaqib Shamim, Surjit Singh, Pradeep Dwivedi, Rajesh Jhorawat, Shoban Babu Varthya.

  Chronic kidney disease (CKD) is associated with reflecting innate immune impairment. Chronic inflammation, oxidative stress, metabolic dysregulation, and prolonged uraemia are the primary causes of this condition. Monocytes, macrophages, and their progenitors may undergo drastic epigenetic changes in response to these systemic stresses. This has lowered the activation of histone marks, such as H3K4me3, and destabilised repressive marks, like H3K9me3. Critical immune response genes are silenced by chromatin closure. This epigenetic change exhausts the immune system and impairs its ability to clear pathogens. This causes 'uraemic immunodeficiency', a poor vaccination response, and increased susceptibility to infection. On the other hand, the Bacillus Calmette-Guérin (BCG) vaccination may produce trained immunity, a favourable innate immunological memory. BCG stimulates the NOD2 and Akt/mTOR pathways. This increases H3K4me3 near cytokine gene promoters and stabilises H3K9me3 in non-essential genomic areas. This progressive remodelling creates transcriptionally permissive chromatin that increases inflammatory reactivity. This increases the phagocytosis and antimicrobial activity of monocytes, macrophages, and neutrophils. BCG also reprogrammes hematopoietic stem and progenitor cells to create sustained myeloid cells. Comparing CKD-induced immunological paralysis to BCG-induced immune extension indicates that metabolic and environmental factors strongly influence the innate immune epigenome. BCG-induced trained immunity may represent a low-cost, host-directed strategy to reduce infection susceptibility and improve vaccine responsiveness in patients with CKD. This review shows that the BCG restores chromatin accessibility and transcriptional ability to treat CKD-induced immunological deficiencies. To restore immunological function in CKD patients, BCG-based therapies and epigenetic modulators should be studied.

Keywords:  BCG vaccine; Chronic kidney disease (CKD); Epigenetic reprogramming; Histone modifications (H3K4me3, H3K9me3); Trained immunity; Uraemic immunodeficiency

DOI:  https://doi.org/10.25259/IJMR_131_2026
Front Med (Lausanne). 2026 ;13 1950422

Trained immunity-based mucosal immunotherapies for preventing respiratory infections: a translational, evidence-graded appraisal of platforms, populations, and the protection-immunopathology balance.

Yanhong Lyu, Fengjun Zhang, Qiong Zhao.

  Conventional respiratory vaccines protect through antigen-specific immunity, leaving broad gaps against antigenically diverse and emerging pathogens and inducing little protection at the airway surface itself. Trained immunity, the durable epigenetic and metabolic reprogramming of innate immune cells and their bone marrow progenitors, offers antigen-agnostic, heterologous protection and can be induced directly at the respiratory mucosa, providing a mechanistic rationale for a new class of prophylactic immunotherapies. Here we appraise this field from a clinical-translational, evidence-graded standpoint, integrating three interdependent axes. We first compare the principal inducer platforms (bacille Calmette-Guérin, β-glucan and other pattern-recognition-receptor ligands, inactivated polybacterial preparations, and viral vectors) together with the intranasal, sublingual, and inhaled routes through which they deposit innate memory, showing that platform and route jointly govern the quality, location, and durability of protection. We then grade the clinical evidence population by population, which forms a gradient rather than a uniform endorsement: strongest for sublingual MV130 in childhood recurrent wheeze, moderate for bacille Calmette-Guérin in older adults and for MV130 in chronic obstructive pulmonary disease, and preliminary but promising in immunocompromised hosts. Throughout, we apply the protection-vs.-immunopathology balance as a critical lens, distinguishing host resistance from disease tolerance and highlighting the biomarkers and patient-selection strategies needed to steer benefit over harm. We conclude that trained immunity-based mucosal immunotherapy is best advanced not as a uniform promise but as a disciplined program aligning standardized interventions, mechanism-matched trial endpoints, and prospective biomarkers, positioning it as a credible complement to antigen-specific respiratory vaccines.

Keywords:  BCG; MV130; disease tolerance; mucosal immunotherapy; respiratory infections; trained immunity

DOI:  https://doi.org/10.3389/fmed.2026.1950422
Front Aging Neurosci. 2026 ;18 1973833

Gut-brain immune dysregulation in Parkinson's disease: a hypothesis-forming narrative review of trained immunity.

Mingke Tang, Jingxian Li, Chuanzhang Zhang, Ruoxin Tu, Shun Wang.

  Parkinson's disease (PD) is increasingly understood as a multisystem disorder in which gastrointestinal dysfunction, immune remodeling, protein aggregation, and central neurodegeneration interact across the disease course. Although gut microbiota alterations are repeatedly reported in PD, taxonomic differences alone do not explain how peripheral ecological signals acquire neurological relevance. This review therefore focuses on immune translation: the processes through which dysbiosis, microbial metabolites, intestinal barrier stress, and mucosal inflammation may reshape peripheral immunity and lower the threshold for central neuroinflammatory responses. Particular attention is given to trained immunity as a mechanistic framework that may connect repeated low-grade gut-derived stimulation with persistent innate immune reprogramming. Direct evidence that trained immunity drives PD remains limited; the concept is presented as a testable bridge rather than an established causal pathway. We integrate this framework with age-related immunosenescence and inflammaging, enteric nervous system vulnerability, vagal communication, alpha-synuclein pathology, blood-brain barrier signaling, and microglial priming. Human microbiome studies, Parkinsonian animal models, LPS-based innate immune-memory paradigms, and emerging intervention trials are considered according to their evidentiary level and major confounders, including constipation, diet, medication exposure, geography, and disease stage. The resulting model accommodates body-first, brain-first, and mixed trajectories rather than assigning a universal gut origin to PD. Therapeutically, the evidence supports a shift from nonspecific microbiome normalization toward mechanism-matched strategies that combine ecological, immune, metabolic, and clinical biomarkers. Longitudinal prodromal cohorts and integrated multi-omics with immune phenotyping will be essential to determine whether gut-brain immune signatures identify causal pathways, progression markers, or treatment-responsive subgroups.

Keywords:  Parkinson’s disease; alpha-synuclein; gut microbiota; gut-brain axis; inflammaging; microglia; neuroinflammation; trained immunity

DOI:  https://doi.org/10.3389/fnagi.2026.1973833
Res Sq. 2026 Aug 14. pii: rs.3.rs-10008020. [Epub ahead of print]

Inhibiting trained immunity in Duchenne muscular dystrophy enhances muscle regeneration and reduces fat deposition.

Lorenza Esposito, Andrea Bracaglia, Anna Picca, Giorgia Cavioli, Veronica Ruggieri, Carmine Nicoletti, Luca Madaro, Carles Sanchez Riera, Dario Coletti, Anna Ranzenigo, Giulia Maria Davighi, William Wang, Judit Morla-Folch, Nicola Tumino, Paola Vacca, Emanuele Marzetti, Marina Bouche, Abram Jp Teunissen, Biliana Lozanoska-Ochser.

Background Trained immunity (TI) refers to a hyperresponsive functional state of innate immune cells, such as inflammatory monocytes, induced in response to a variety of stimuli including signals released from damaged tissue, and characterised by increased cytokine production. Inflammatory monocytes play a critical role in Duchenne muscular dystrophy (DMD) by driving chronic muscle inflammation and disease progression. In this study we examined the role of trained immunity in dystrophic muscle pathology by specifically targeting this process in monocytes. Methods We used the mdx mouse model of DMD to investigate TI induction in splenic and bone marrow monocytes isolated during the peak of muscle injury and inflammation. Transcriptional changes in monocytes were examined by performing RNA-Seq, while cytokine production following stimulation with LPS was examined by multiplex ELISA. Mice were treated for two weeks with twice weekly i.v. injections of apolipoprotein A1-based, rapamycin-loaded nanobiologics (mTORi-NB) to specifically target TI in monocytes within the bone marrow and the spleen through the inhibition of the mTOR pathway which plays a central role in TI induction. Inhibition of TI in monocytes was assessed in vitro by measuring cytokine production following stimulation with LPS. Satellite cells and FAPs were sorted from limb muscles and cultured in vitro to assess the effect of the treatment on their proliferation and differentiation properties. Results Dystrophic muscle injury was associated with transcriptional changes in mdx monocytes linked to chromatin and metabolic remodelling as well as with hyperproduction of proinflammatory cytokines, consistent with TI induction. Treatment of mdx mice with mTORi-NB resulted in improved skeletal muscle regeneration and reduced fat deposition. In vitro experiments confirmed the enhanced myogenic properties in satellite cells and reduced adipogenesis in FAPs mediated by the inhibition of TI in monocytes. Conclusions Dystrophic muscle injury induces TI in both bone marrow and splenic monocytes characterised by hyperproduction of proinflammatory cytokines. Targeting TI specifically in monocytes through mTOR inhibition enhances muscle regeneration and reduces intramuscular fat deposition. Overall, our findings suggest that inhibition of TI represents a promising therapeutic strategy to slow DMD progression.

DOI: https://doi.org/10.21203/rs.3.rs-10008020/v1
Front Immunol. 2026 ;17 1940736

Metabolic-epigenetic imprinting of macrophages in endometriosis: a working model for lesion persistence and treatment.

Yaru Wang, Wanqiu Xia, Xueting Su, Lei Fang.

  Endometriosis is an estrogen-dependent inflammatory disorder that often persists or returns even after visible lesions have been removed. The behavior of peritoneal macrophages may help explain this clinical durability. These cells participate in lesion implantation, vascularization, fibrosis, defective immune clearance, and pain, but it is uncertain why disease-supporting phenotypes are maintained. We argue that repeated exposure to the endometriotic niche may leave macrophages with a metabolically conditioned epigenetic memory rather than only a short-lived polarization state. Lactate, succinate, iron, oxysterols, and glutamine-derived metabolites could alter cellular metabolism while also providing substrates, cofactors, or inhibitors for chromatin-modifying enzymes. Histone lactylation and TET/JmjC-regulated methylation states are plausible molecular records of this exposure, although neither has yet been followed from metabolite to persistent mark and macrophage function in human disease. At present, the most direct endometriosis-specific support comes from a TGF-β1/CCL2-induced TET3 program associated with let-7 repression, inflammatory cytokine production, and macrophage survival. Other proposed circuits, including lactate-lactylation coupling and macrophage-stromal exchange of glycolytic signals, remain incomplete. This distinction matters: established findings support parts of the model, but not yet the entire causal chain. A memory state should be experimentally identifiable by its persistence after stimulus withdrawal, transferability, metabolic dependence, and reversibility. If experiments satisfy these criteria, the retained macrophage state would become a plausible non-hormonal target. The relevant test would be whether changing that state produces a lasting loss of lesion-supporting function instead of a brief reduction in downstream inflammation.

Keywords:  TET3; endometriosis; histone lactylation; immunometabolism; macrophage memory; trained immunity

DOI:  https://doi.org/10.3389/fimmu.2026.1940736
Signal Transduct Target Ther. 2026 Oct 06. pii: 427. [Epub ahead of print]11(1):

Source-specific priming of lung NK cells by Pseudomonas LPS enhances resistance to bacterial pneumonia.

Xin Yang, Haoqi Liu, Quanhui Xu, Jian Peng, Huanxing Sun, Deanna Hausman, Ximing Ran, Erica Herzog, Ye Zhang, F Susan Wong, Xin Chen, Liqiang Guo, Han Ge, Yanlong Hong, Lei Zhang, Li Wen, Ruirui Wang, Guang Ji.

Bacterial pneumonia is a major cause of morbidity and mortality in elderly individuals, yet how mucosal innate immunity changes with age remains unclear. We detected bacterial DNA, particularly signatures of Pseudomonas, in the circulation of healthy elderly individuals, suggesting that chronic exposure to low-dose microbial components occurs during aging. Using murine models, we found that intratracheal delivery of a low dose of Pseudomonas aeruginosa lipopolysaccharide (LPS) strongly protected against bacterial pneumonia through a microbiota-dependent mechanism, whereas Escherichia coli LPS had no detectable protective effect. This protective response occurred in the absence of adaptive immunity and was mediated by lung-resident natural killer (NK) cells. Transcriptomic profiling revealed that P. aeruginosa LPS selectively upregulated the complement receptor C3aR1 in pulmonary NK cells, increasing their IFN-γ production and LFA-1-dependent adhesion to target cells. Adoptive transfer of P. aeruginosa LPS-conditioned pulmonary NK cells conferred protection to naïve recipients, whereas silencing C3aR1 abrogated this effect. This localized innate training occurred without systemic inflammation and required the presence of a commensal microbiota. These findings reveal that structurally distinct LPS from P. aeruginosa programs lung NK cells toward a C3aR1-driven, high-affinity effector state that enhances resistance to bacterial pneumonia. Source-specific innate conditioning of mucosal NK cells may provide a tissue-targeted strategy to strengthen pulmonary host defense, particularly in aging populations vulnerable to respiratory infections.

DOI: https://doi.org/10.1038/s41392-026-02832-z
Proc Natl Acad Sci U S A. 2026 Oct 13. 123(41): e2612173123

Transcriptional regulation and function of GPR18 in macrophage subtype specification.

Hebe Agustina Mena, Andreas Patsalos, Jake Altomare, Filippa Davidsson, Gergely Nagy, Wilhelm K Berger, Blenda Wong, Allison Rahtes, Gabrielle Fredman, Laszlo Nagy, Matthew Spite.

  Resolution of inflammation is mediated in part by agonists that engage immune cells to dampen inflammatory signaling, promote phagocytic functions, and facilitate tissue repair. G protein-coupled receptor 18 (GPR18) has emerged as an important proresolving receptor that is activated by endogenous mediators including Resolvin D2. However, very little is known about how GPR18 expression is controlled in immune cells, and its cell-autonomous roles during resolution of inflammation remain of interest. Here, we elucidated transcriptional and epigenetic regulation of Gpr18 in macrophages (MFs). We identified binding of monocyte/macrophage lineage-determining transcription factors (LDTFs) including PU.1, IRF8, and RUNX1 at the Gpr18 locus in the basal state in murine bone marrow-derived macrophages (BMDM). We found that Gpr18 is highly induced in BMDM by inflammatory stimuli including interferon gamma (IFNγ) and ligands for multiple toll-like receptors. Motif analysis predicted enrichment for LDTFs and signal-dependent TFs including nuclear factor κB (NFκB) and interferon regulatory factors (IRF) at the Gpr18 locus. Stimulation of BMDM with lipopolysaccharide (LPS) or IFNγ increased the binding of NFκB p65 and IRF1 at the Gpr18 locus, which played a causal role in the induction of Gpr18 by LPS or IFNγ, respectively. Mice with myeloid deficiency of Gpr18 had increased tissue swelling and accumulation of "inflammatory" Ly6Chi monocytes/MFs during contact hypersensitivity, which was recapitulated during acute peritonitis and led to altered transcriptomes of resolution-phase MFs. These results demonstrate that inflammatory signaling primes MFs for resolution in part by inducing Gpr18, which plays a cell-autonomous role to regulate MF phenotypic transitions.

Keywords:  G protein–coupled receptors; macrophages; resolution of inflammation

DOI:  https://doi.org/10.1073/pnas.2612173123
Int Immunopharmacol. 2026 Oct 07. pii: S1567-5769(26)01355-X. [Epub ahead of print]190 117507

Lactobacillus gasseri suppresses methionine-driven epigenetic programming of trained immunity-like priming to attenuate metabolic dysfunction.

Zheyu Fan, Yahan Yu, Chaorun Dong, Wenjie Bu, Yi Yu, Sisi Li, Zhiguo Wang, Yunlong Bai.

  Trained immunity-like epigenetic priming contributes to persistent metabolic inflammation in type 2 diabetes mellitus (T2DM), but the upstream metabolic and microbiota-dependent regulatory mechanisms remain unclear. Here, we performed an exploratory study to examine whether Lactobacillus gasseri (Lact. gasseri) attenuates metabolic dysfunction by suppressing methionine-dependent epigenetic priming of innate immune cells, and to characterize how metformin regulates Lact. gasseri colonisation in the intestine. A diabetes-prone mouse model was established using high-fat diet (HFD) and low-dose streptozotocin (STZ); a standard-chow plus STZ group was included to control for the direct β-cell toxicity of STZ. Metabolic phenotypes, histopathology, inflammatory responses, and intestinal barrier function were assessed. Bone marrow-derived macrophages (BMDMs) were rested ex vivo for 4 days in the absence of any in vivo stimulus and then subjected to an unrelated secondary LPS/IFN-γ challenge in order to evaluate primed responsiveness, and methionine-one‑carbon metabolism, H3K4me3, and cytokine expression were analysed by RT-qPCR, western blotting, ELISA and ChIP-qPCR. Lact. gasseri significantly reduced diabetes incidence and improved glucose tolerance and insulin sensitivity, ameliorated dyslipidaemia and pancreatic injury in HFD/STZ-treated mice. Mechanistically, Lact. gasseri was associated with reduced methionine availability and with lower absolute abundance of systemic and bone marrow methyl donors, accompanied by decreased H3K4me3 at the Il-1β promoter and attenuated IL-1β-mediated trained immunity-like priming. Methionine restriction in macrophages recapitulated these effects, whereas methionine replenishment restored histone methylation and IL-1β maturation, supporting a metabolic-epigenetic axis while not excluding contributions from other nutrient-sensitive pathways. Notably, metformin enhanced intestinal colonisation of Lact. gasseri without directly promoting bacterial growth in vitro, an effect accompanied by improved mucus barrier integrity and concordant upregulation of P53 and MUC2. Because no combined Lact. gasseri plus metformin arm was included in vivo, metabolic synergy was not tested in this study. Together, these exploratory findings describe a candidate microbiota-linked mechanism in which Lact. gasseri constrains methionine-dependent epigenetic priming of innate immune cells, connecting intestinal nutrient availability to systemic inflammatory memory and providing a rationale-rather than proof-for probiotic-drug combination strategies in T2DM.

Keywords:  Epigenetics; Gut microbiota; Lactobacillus gasseri; Methionine metabolism; Trained immunity-like priming; Type 2 diabetes

DOI:  https://doi.org/10.1016/j.intimp.2026.117507
Cell Mol Immunol. 2026 Oct 09.

The H3K27me3-NR1D1-IFN-γ axis in trained macrophages induced by early respiratory virus infection drives non-T2 asthma in children.

Hanglin Li, Boyang Zheng, Beibei Qin, Wenjian Li, Jia Gao, Mengmeng Li, Wenna Ji, Junhai Wang, Caixia Li, Ling Zhang, Jiaqi Liang, Yiming Zhang, Lijie Zhao, Meiqian Wang, Xiaoqing Zheng, Yuqing Deng, Ruihong Zeng.

  Unlike that of T2 asthma, the pathophysiology of non-T2 asthma remains largely unexplored. However, increasing evidence supports a role for trained macrophages in asthma. In this study, we utilized a non-T2 asthma mouse model associated with early respiratory viral infection to identify the H3K27me3-NR1D1-IFN-γ axis in lung-trained macrophages, which drives non-T2 asthma by promoting Th1 differentiation. Early infection combined with allergen sensitization induced the formation of trained macrophages, which displayed hyperactive methionine cycling and elevated levels of S-adenosylmethionine (SAM). As a substrate for methyltransferase, SAM enhanced the trimethylation of H3K27, subsequently suppressing the expression of the nuclear receptor subfamily 1 group D member 1 (NR1D1) gene through enrichment at its promoter. Interestingly, NR1D1 interacted with the Ifng gene and negatively regulated its expression. High levels of IFN-γ from trained macrophages were observed because NR1D1 was inhibited by elevated H3K27me3 levels. Following allergen challenge, the increased expression of IFN-γ, MHC-II, and CD80/CD86 in trained macrophages positively regulated the activation and differentiation of Th1 cells, which subsequently produced more IFN-γ, thereby promoting non-T2 asthma. Consistently, in patients with asthma, peripheral blood mononuclear cells (PBMCs) and monocytes downregulated NR1D1 expression, resulting in elevated IFN-γ levels. Conversely, treatment of patient monocytes with an NR1D1 agonist led to a marked decrease in IFN-γ production. In mice, non-T2 asthma was significantly inhibited by either the inhibition of H3K27me3, the activation of NR1D1, or the neutralization of IFN-γ. Our results demonstrate that the H3K27me3-NR1D1-IFN-γ axis in lung-trained macrophages, which is associated with early infection, drives non-T2 asthma during childhood in mice. Consequently, SAM, NR1D1, and IFN-γ may serve as potential drug targets for the treatment of non-T2 asthma.

Keywords:  Early respiratory virus infection; H3K27me3-NR1D1-IFN-γ axis; Non-T2 asthma; SAM; Trained macrophages

DOI:  https://doi.org/10.1038/s41423-026-01470-3
Cell Metab. 2026 Oct 07. pii: S1550-4131(26)00383-9. [Epub ahead of print]

Histone lactylation scarring transmits metabolic and epigenetic memory across the gut-liver axis.

Heng Dong, Jinyang Li, Daowei Yang, Sheng Zhou, Abhinav Choubey, Tiantian Wang, Ruobing Du, Shiyan Li, Huilian Shi, Xiaolei Zhu, Rong Wang.

  Ulcerative colitis (UC) remission does not abolish susceptibility to metabolic dysfunction-associated steatotic liver disease (MASLD), but the mechanism linking prior intestinal inflammation to delayed liver injury remains unclear. We establish gut-liver axis memory transduction as an epigenetic-cellular-organ cascade in which inflammatory history is molecularly encoded and redeployed across organs. LCN2+ colonic macrophages persist after colitis resolution and retain heightened glycolysis together with durable histone H3K9 L-lactylation (H3K9la). These macrophages maintain a permissive memory state during remission and traffic to the liver, where they amplify steatosis under subsequent HFD challenge. Mechanistically, BRG1 cooperates with CEBPB at H3K9la-marked chromatin to sustain Lcn2 and Pkm transcription in a feed-forward circuit. Myeloid-specific Smarca4 deletion or pharmacological interruption of macrophage trafficking attenuates macrophage memory and protects against MASLD. Together, our findings define H3K9la-centered macrophage memory as a mobile pathogenic imprint that links prior colitis to increased susceptibility to metabolic liver disease.

Keywords:  BRG1–CEBPB complex; H3K9 lactylation; LCN2(+) macrophages; MASLD; UC remission; gut-liver axis; metabolic memory

DOI:  https://doi.org/10.1016/j.cmet.2026.09.008
Cell. 2026 Oct 06. pii: S0092-8674(26)01126-8. [Epub ahead of print]

A non-canonical function of glutathione to suppress ferroptosis via FSP1.

Jing Han, Yu-Dan Zhang, Shuo Liu, Li Yang, Shuang-Li Sun, Ben Zhang, Ao-Kun Liu, Ling-Fan Zhu, Rong Wang, Dan-Dan Song, Xiao Zhuang, Yi-Jia Gao, Jing-Xin Li, Wen-Fei Li, Rong-Rong He, Heng-Xing Zhou, Lu Yu, Shi-Qing Feng, Ren-Jie Chai, Bo Chu.

  It is well established that glutathione (GSH) is mainly utilized by glutathione peroxidase 4 (GPX4) to diminish peroxidized phospholipids and defend against ferroptosis. However, we found that GSH robustly protects a variety of GPX4 knockout (KO) cells from ferroptosis, thus indicating that there is an alternative pathway for GSH to suppress ferroptosis. By carrying out genome-wide CRISPR-Cas9 screening, we identified that ferroptosis suppressor protein 1 (FSP1) is the key factor mediating the GPX4-independent protective effect of GSH. Mechanistically, FSP1 uses GSH to generate reduced ubiquinone, which scavenges oxidized lipids and suppresses ferroptosis. Inhibition of FSP1 abolishes this GSH-dependent ferroptosis protection both in vitro and in vivo. Distinct from NAD(P)H-mediated ubiquinone reduction, GSH-stimulated generation of reduced ubiquinone via FSP1 is independent of flavin adenine dinucleotide (FAD). Together, our work clarifies a new mechanism of GSH-mediated ferroptosis suppression, thus highlighting the potential that targeting GSH metabolism should be beneficial for ferroptosis-related diseases whether or not it is related to GPX4.

Keywords:  FSP1; ferroptosis; glutathione metabolism; ubiquinone reduction

DOI:  https://doi.org/10.1016/j.cell.2026.09.024
Sci Signal. 2026 Oct 06. 19(958): eaeb2392

Metabolic reprogramming of pathogenic CD4+ T helper cells attenuates inflammatory bowel disease in mice.

Shravan K Mishra, Leena M Abdelrahman, Hyun Se Kim Lee, Lucía Valenzuela-Pérez, Dina F Manna, Tanner J Abram, Lama Mohamed Ali, Heidi M Davidson, Omar M Hassan, William A Faubion, Petra Hirsova, Adebowale O Bamidele.

CD4+ effector T helper 1 (TH1) cells drive inflammatory bowel disease (IBD). Here, we investigated how integrated signaling, metabolic, and epigenetic programs sustain their pathogenic persistence. We found that enforcing mitochondrial pyruvate metabolism with methyl pyruvate (MePyr) suppressed TH1 cell effector function and induced the acquisition of a regulatory-like phenotype. MePyr suppressed the activity of glycogen synthase kinase 3β (GSK3β), promoting a metabolic shift from glycolysis toward oxidative phosphorylation (OXPHOS) and limiting the accumulation of intracellular acetyl-CoA. This metabolic reprogramming decreased histone H3 acetylation at genes encoding inflammatory cytokines, thereby decreasing TH1 cell-associated gene expression. Restoration of inflammatory cytokine production by acetate supplementation or histone deacetylase inhibition established acetyl-CoA-dependent histone acetylation as a mechanistic link between metabolic flux and effector function. Conversely, the cytokine interleukin-21 enhanced TH1 cell effector activity by promoting a GSK3β-dependent shift from OXPHOS to glycolysis. Single-cell transcriptomic analysis of Crohn's disease tissue revealed enrichment of glycolytic gene programs in nonregulatory CD4+ T cells. Consistent with these findings, pharmacologic inhibition of GSK3β attenuated disease severity in a T cell-transfer mouse model of colitis. Together, these findings identify a GSK3β-dependent metabolic-epigenetic axis that sustains TH1 cell pathogenicity and highlight GSK3β as a potential therapeutic target for IBD.

DOI: https://doi.org/10.1126/scisignal.aeb2392