bims-imicid 2026-04-12 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2026–04–12
37 papers selected by
Dylan Gerard Ryan, Trinity College Dublin

Metabolite sensing receptors in macrophage reprogramming: from inflammation to resolution.
Editorial: Immunometabolism: exploring the nexus of metabolism and immune function in health and disease.
iNOS modulates inflammatory responses in an NO-independent manner through direct interaction with IRG1 in mitochondria.
The metabolic environment within solid tumors drives a complex crosstalk between macrophages and NK cells.
Pharmacologic DPP-4 inhibition promotes CD8⁺ T cell metabolic fitness to enhance anti-tumor activity.
Dietary conjugated linoleic acid enhances resistance to Salmonella infection by promoting PPARγ-mediated metabolic reprogramming and effector function in CD8⁺ T cells.
Ets1-dependent Mek-Erk signaling drives adipose tissue macrophage anti-inflammatory polarization to ameliorates insulin resistance.
Correcting Mitochondrial Complex I Defect in Tumor-Associated Natural Killer Cells Potentiates Immunotherapy for Glioblastoma.
Integrated Proteomics and Metabolomics Analyses Reveal That Phosphatidylethanolamine Reprograms Macrophage Immunometabolism and Attenuates LPS-Driven Inflammation.
Metabolic reprogramming in tumor-associated cells of hematologic malignancies: mechanisms, crosstalk networks, and therapeutic implications in the tumor microenvironment.
IGF2BP2 Deficiency in Macrophages Impairs Migration, Reprograms Metabolism, and Limits Tumor Progression.
Epigenetic, epitranscriptomic, and metabolic control of T cell exhaustion.
Microbial metabolism of methotrexate produces a STAT3 signaling molecule that alleviates gut inflammation.
Metabolic reprogramming by caloric restriction enhances acute phase virological control and reduces chronic inflammation in SIV-infected rhesus macaques.
Arachidonic Acid Metabolism in PMN-MDSCs Suppresses Antitumor Capacity of T cells in KRAS-Mutant Cholangiocarcinoma.
Distinct inflammatory programming of thoracic cavity white adipose immune cells regulates influenza pathogenesis.
Dual Energy Depletion by Zinc/Copper Disruptor to Potentiate Cuproptosis and Pyroptosis for Enhanced Tumor Immunotherapy.
Mitochondrial iNOS blocks itaconate production by interacting with IRG1.
Crosstalk between cytokines and tryptophan metabolism: Therapeutic potential for immune effector cell-associated neurotoxicity syndrome.
High Glucose Triggers Macrophage Senescence Through Mitochondrial Dysfunction and Mitophagy Impairment.
Epstein-Barr Virus Latent Membrane Protein 1 Suppresses Ferroptosis via Pentose Phosphate Pathway and Glutathione Metabolism.
Hexokinase 3 promoted cytokine production of monocytes by targeting metabolic reprogramming and histone lactylation in sepsis.
Targeting KIF20A blocks lactylation modification to suppress immune escape in hepatocellular carcinoma.
ARID1A deficiency-driven reprogramming of polyamine metabolism promotes endometrial cancer malignancy and immune escape.
Chitinase-like proteins de-N-glycosylating CD36 modify cholesterol metabolism in atherosclerotic macrophages.
Uncovering Mediating Mechanisms Linking Immune Cells to Systemic Lupus Erythematosus: Insights into Mendelian Randomization.
Lactate drives immune resistance via a pharmaceutically reversible H3K18la-KIF20A-c-Myc-PD-L1 axis in hepatocellular carcinoma.
Linking inflammation, metabolic dysfunction, and neurodegeneration: a comprehensive review of TLR2 pathways in type 2 diabetes.
Lipid metabolism reprogramming shapes the immune landscape in the tumor microenvironment.
FNIP1 Modulates B Cell Receptor Signaling Strength by Coordinating Metabolism During Development.
Aberrant long-chain fatty acids metabolism and its interplay with immuno-inflammatory responses in relapsing-remitting multiple sclerosis.
Exploring brain glucose metabolism in multiple sclerosis: A deuterium metabolic imaging study.
Vancomycin eliminates gut deoxycholic acid, restoring ER proteostasis in ILC2s and relieving colitis.
Integrated transcriptomics, proteomics, and metabolomics analysis reveals newcastle disease virus reshapes glycerophospholipid metabolism.
Peptide hydrogel boosts the cytotoxic and metabolic fitness of Vγ9Vδ2 T cells in melanoma immunotherapy.
RNA binding protein Pcbp1 maintains mitochondria integrity to promote antibody production and germinal center response.
IL-13 promotes accumulation of esophageal epithelial mitochondria with translational implications for eosinophilic esophagitis.

Inflamm Res. 2026 Apr 10. pii: 91. [Epub ahead of print]75(1):

Metabolite sensing receptors in macrophage reprogramming: from inflammation to resolution.

Shubham Kumar Rai, Saloni Gupta, Pranita P Sarangi.

   BACKGROUND: Macrophages are central to innate immunity, orchestrating both the inflammatory and resolution phases of host defense. Emerging evidence indicates that immunometabolic crosstalk critically dictates macrophage polarization and functions. Disruptions in cellular metabolism can impair these regulatory mechanisms, leading to dysfunctional immune responses associated with various disease pathologies. A key aspect of this regulation involves metabolite-sensing receptors that detect changes in intracellular metabolic intermediates and in extracellular metabolites derived from the diet, host tissues, and the microbiome.
METHODS: We have conducted a literature review of original research and review articles on metabolite-sensing receptors and their roles in immune cell function, drawn from central databases including PubMed and Google Scholar.
RESULTS AND CONCLUSION: A major class of extracellular metabolite-sensing receptors is G-protein-coupled receptors (GPCRs), which can directly or indirectly modulate macrophage activation, migration, cytokine production, and metabolic reprogramming. By fine-tuning macrophage-specific functions, metabolite-sensing receptors act as critical regulatory nodes in both inflammation and immune homeostasis, beyond their canonical role in sensing metabolic cues. This review provides a comprehensive overview of the metabolite-sensing receptor interactome, highlighting their central role in macrophage biology and underscoring their potential as therapeutic targets in inflammatory and metabolic diseases.

Keywords:  GPCRs; Immunometabolism; Inflammation; Macrophages; Metabolic reprogramming; Metabolites; Resolution

DOI:  https://doi.org/10.1007/s00011-026-02240-7
Front Immunol. 2026 ;17 1827639

Editorial: Immunometabolism: exploring the nexus of metabolism and immune function in health and disease.

Eric Henrique Roma, Juliana Lauar Gonçalves.



Keywords:  immune response; immunometabolic regulation; immunometabolism; infectious diseases; inflammation; non-infectious chronic diseases

DOI:  https://doi.org/10.3389/fimmu.2026.1827639
Nat Metab. 2026 Apr 10.

iNOS modulates inflammatory responses in an NO-independent manner through direct interaction with IRG1 in mitochondria.

Marina Diotallevi, Carlos Outeiral, Priyanka Patel, Gareth S D Purvis, Surawee Chuaiphichai, Thomas Nicol, Faseeha Ayaz, Daniel A Nissley, Ganna O Krasnoselska, Svenja Hester, John H McVey, Roman Fischer, Benedikt Kessler, Charlotte M Deane, Raymond J Owens, Keith M Channon, Mark J Crabtree.

Nitric oxide (NO) has fundamental roles in numerous physiological and pathophysiological processes. In macrophages, NO produced by inducible nitric oxide synthase (iNOS) modulates metabolic changes that are essential to macrophage activation and plasticity, driving the characteristic metabolic switch from oxidative phosphorylation to glycolysis1,2. Itaconate, derived from the TCA cycle by decarboxylation of cis-aconitate by IRG1 (also referred to as CAD, ACOD1), is one of the most upregulated metabolites during the inflammatory response3. Itaconate regulates macrophage polarization by electrophilically modifying cysteines of key enzymes that control inflammatory states (such as ATF3, Jak1, IFNβ), participate in glycolysis (for example, GAPDH, LDHA) and limit oxidative stress through structural competitive inhibition of succinate dehydrogenase4-9. We recently reported that macrophages that are deficient in iNOS, and subsequent NO generation, produce strikingly higher levels of intracellular itaconate (up to ~15-fold) compared to wild-type cells when stimulated with inflammatory cytokines1,2,10. Here we show that iNOS inhibits IRG1 activity and itaconate levels through a conformation-dependent protein-protein interaction rather than through the production of NO. Using a variety of biochemical and computational approaches, we show that a direct interaction between iNOS and IRG1 occurs within mitochondria, in mouse and human cells, and that it depends on binding of the cofactor BH4 to iNOS but does not require its capability to produce NO. Our findings reveal a non-canonical cellular function for iNOS that places it at the centre of a signalling hub, linking redox signalling and metabolism to modulation of the inflammatory response in macrophages.

DOI: https://doi.org/10.1038/s42255-026-01492-1
Front Immunol. 2026 ;17 1726590

The metabolic environment within solid tumors drives a complex crosstalk between macrophages and NK cells.

Didem Cakirsoy Akyoney, Joel Nordin, Samir El Andaloussi, Evren Alici.

  The tumor microenvironment (TME) exerts significant metabolic limitations that influence the activity of invading immune cells. Among them, macrophages and natural killer (NK) cells are essential for coordinating anti-tumor immunity; however, the metabolic conditions of solid tumors have a significant impact on their functional states. Emerging evidence indicates that metabolic competition and nutrition availability regulate the dynamic interactions between these two innate immune populations, eventually influencing immune activation, suppression, and tumor growth. In this review, we discuss how key metabolic factors, including glucose depletion, lipid metabolism, hypoxia, and lactate accumulation, reshape NK cell activity and macrophage polarization in the TME. We emphasize how cytokine signaling and spatial organization within tumors influence NK-macrophage interactions, resulting in either synergistic anti-tumor responses or immunosuppressive networks. Finally, we explore novel therapeutic approaches designed to target metabolic pathways to restore NK cell function and reprogram macrophages toward pro-inflammatory phenotypes. Understanding the metabolic regulation of NK-macrophage interactions could provide new opportunities to improve immunotherapy efficacy in solid tumors.

Keywords:  anti-tumor immunity; crosstalk; macrophage; metabolic competition; natural killer cells (NK cells); solid tumor; tumor associate macrophages (TAM)

DOI:  https://doi.org/10.3389/fimmu.2026.1726590
bioRxiv. 2026 Apr 03. pii: 2026.03.31.715681. [Epub ahead of print]

Pharmacologic DPP-4 inhibition promotes CD8⁺ T cell metabolic fitness to enhance anti-tumor activity.

Oriana Y Teran Pumar, Elton L VanNoy, Abigail Haffey, Durga Prasad Gannamedi, Christine Isabelle Rafie, Dylan Scott Lykke Harwood, Julia R Benedetti, Christine Ann Pittman Ballard, Erika Ciervo, Pedro Henrique Assenza Tavares Coroa, Payal Grover, Brandon Emanuel León, Jonathan Mitchell, Asmita Pathak, Bruno Colon, Lyenne El Ghorayeb, Laura O'Sullivan, Venu Venkatarame Gowda Saralamma, Clara Lopez Ruiz, Natasha Khatwani, Surinder Kumar, Priyamvada Rai, Jonathan Schatz, Ashish Shah, Zev A Binder, Michele Ceccarelli, Quinn T Ostrom, Bjarne Winther Kristensen, Erietta Stelekati, Dionysios C Watson, David B Lombard, Dalia Haydar, Defne Bayik.

Metabolic dysfunction is a hallmark of CD8 + T cell exhaustion in the tumor microenvironment. Thus, there is growing interest in developing strategies that enhance anti-tumor functions of CD8 + T cells via metabolic reprogramming. Here, we identify dipeptidyl peptidase 4 (DPP-4) as a previously unknown regulator of CD8 + T cell function and metabolism. We discovered that DPP-4 is upregulated in exhausted CD8 + T cells. Pharmacological inhibition of DPP-4 with the FDA-approved anti-diabetic drug sitagliptin transcriptionally and metabolically reprogrammed CD8 + T cells, increasing spare mitochondrial respiratory capacity, proliferation, cytotoxic mediator production, and antigen-specific cancer cell killing capability. The functional effects of sitagliptin were dependent on upregulation of glutamate decarboxylase 1 (GAD1), an enzyme that feeds glutamate into the tricarboxylic acid (TCA) cycle, highlighting a new role for GAD1 in CD8 + T cell respiration and proliferation. We found that systemic inhibition of DPP-4 in preclinical mouse glioblastoma (GBM) models prolongs survival in a CD8 + T cell-dependent manner, and retrospective clinical cohort analysis revealed better outcomes in GBM patients using DPP-4 inhibitors. Importantly, preconditioning of Chimeric Antigen Receptor (CAR) T-cells with DPP-4 inhibition enhanced their cytotoxicity, persistence, and therapeutic efficacy in pediatric GBM. Together, our findings provide mechanistic and biological rationale for repurposing readily accessible DPP-4 inhibitors to enhance anti-tumor CD8 + T cell responses.

DOI: https://doi.org/10.64898/2026.03.31.715681
Gut Microbes. 2026 Dec 31. 18(1): 2657625

Dietary conjugated linoleic acid enhances resistance to Salmonella infection by promoting PPARγ-mediated metabolic reprogramming and effector function in CD8⁺ T cells.

Lei Deng, Xinyu Wang, Dinku Yigezaw Mebratie, Yiting Tang, Jiangang Hu, Jingjing Qi, Mingxing Tian, Yanqing Bao, Lihui Zhu, Shaohui Wang.

  Conjugated linoleic acid (CLA) is a dietary lipid that modulates host-microbiota-immune interactions, yet its mechanistic impact on mucosal defense remains unclear. Here, we show that oral CLA supplementation enhances resistance to Salmonella Typhimurium infection and is associated with coordinated changes in gut microbial composition and mucosal immune responses. CLA-enriched commensals, including Dubosiella and Lactobacillus, were associated with increased production of CLA-derived oxylipins and activation of immune surveillance genes. Functionally, CLA pretreatment reduced Salmonella colonization, preserved epithelial integrity, and decreased neutrophilic inflammation without direct antibacterial effects. Single-cell RNA sequencing of ileal intraepithelial lymphocytes revealed that CLA predominantly reprogrammed intestinal CD8⁺ T cells toward an oxidative phenotype and enhanced effector activity. ATAC-seq revealed increased chromatin accessibility at loci associated with metabolic regulation, consistent with transcriptional reprogramming toward oxidative fitness. Mechanistically, CLA directly activated PPARγ signaling to promote mitochondrial biogenesis, oxidative phosphorylation, and the production of IFN-γ and granzyme B in CD8⁺ T cells; pharmacologic inhibition of PPARγ attenuated these effects both in vitro and in vivo. Notably, depletion of CD8⁺ T cells eliminated CLA-mediated protection and abolished early restriction of bacterial dissemination at Peyer's patches and mesenteric lymph nodes. Although CLA enhanced CD8⁺ T-cell effector programs, antibiotic depletion and fecal microbiota transplantation experiments demonstrated that an intact gut microbiota is necessary for effective protection in vivo. Together, these findings identify CLA as a dietary modulator that strengthens mucosal resistance to Salmonella by promoting PPARγ-mediated metabolic reprogramming and enhanced effector fitness in intestinal CD8⁺ T cells.

Keywords:  CD8+ T cells; Conjugated linoleic acid; PPARγ; Salmonella Typhimurium; mucosal immunity

DOI:  https://doi.org/10.1080/19490976.2026.2657625
Cell Rep. 2026 Apr 07. pii: S2211-1247(26)00322-0. [Epub ahead of print]45(4): 117244

Ets1-dependent Mek-Erk signaling drives adipose tissue macrophage anti-inflammatory polarization to ameliorates insulin resistance.

Jiyuan Song, Jiahao Ni, Kunxin Xie, Jinyuan Cao, Wenli Guo, Lei Zhao, Xiaoai Chang, Yu Lu, Peng Sun, Junjie Yu, Chen Qiu, Shufang Yang, Wei Liu, Xiao Han, Kai Li.

  Clinical observations reveal that Mek-Erk inhibitors exert paradoxical immunoregulatory effects on macrophages, yet the mechanisms governing the pathway's specific immunoregulatory outputs remain elusive. Here, we identify Ets1 as a discriminative effector that couples Mek-Erk signaling specifically to anti-inflammatory polarization. We show that while various stimuli activate Erk, only the anti-inflammatory IL-4 activates the transcriptional activity of Ets1 in a Thr38 (T38) phosphorylation-dependent manner. Functionally, myeloid-specific Ets1 knockout mice exhibited exacerbated adipose inflammation and metabolic dysfunction under both physiological and obesity conditions. Mechanistically, Ets1 raises Irf4 expression level via both transcriptional regulation and chromatin remodeling, thereby inducing macrophage anti-inflammatory polarization. Taken together, we demonstrate that Ets1 serves as a critical discriminator activated specifically by IL-4 stimulation but remaining inactive under pro-inflammatory conditions. This bifurcated activation enables Erk signaling to differentially engage downstream effectors based on upstream stimuli, thereby directing macrophage functional specialization.

Keywords:  CP: immunology; CP: metabolism; Ets1; IL-4; Irf4; M2-like polarization; Mek-Erk pathway; adipose inflammation; epigenetic remodeling; immunometabolism; insulin resistance; macrophage

DOI:  https://doi.org/10.1016/j.celrep.2026.117244
Cancer Discov. 2026 Apr 07.

Correcting Mitochondrial Complex I Defect in Tumor-Associated Natural Killer Cells Potentiates Immunotherapy for Glioblastoma.

Nianxin Zhou, Fan Fei, Lin Tang, Peidong Zhang, Wei Wang, Bohao Zheng, Qiuhong Shen, Jing Yue, Liang Huang, Yiwei Du, Xiaoling Liao, Liang Ouyang, Gang Yuan, Jeremy N Rich, Shengtao Zhou, Linjie Zhao.

Despite successful immuno-oncology therapies in other cancers, they largely failed in glioblastoma(GBM). Here, natural killer (NK) cells from glioma patients show impaired oxidative phosphorylation and mitochondrial complex I activity. Multiomics profiling identified complex I subunit NDUFA9 as a critical mediator of NK cell metabolic fitness. Abundance of NDUFA9+ NK cells informed patient outcome. Ndufa9 knockout in NK cells compromised mitochondrial function, anti-tumor efficacy, and memory-like phenotype of NK cells by triggering a metabolic reprogramming toward glutamine dependence. Decreased α-ketoglutarate(α-KG)/succinate ratio in Ndufa9-deficient NK cells mediated widespread epigenetic reprogramming through inducing transcriptionally repressive histone mark H3K27me3 on key immune function genes. Resveratrol-mediated NDUFA9 activation or its overexpression enhanced NK cell anti-GBM function by restoring complex I activity. Together, these findings reveal the critical role of mitochondrial complex I activity in NK cells and highlight its potential as an actionable target to enhance NK cell-based immunotherapy for GBM patients.

DOI: https://doi.org/10.1158/2159-8290.CD-25-0643
J Proteome Res. 2026 Apr 08.

Integrated Proteomics and Metabolomics Analyses Reveal That Phosphatidylethanolamine Reprograms Macrophage Immunometabolism and Attenuates LPS-Driven Inflammation.

Tatiana Maurício, Bruno Neves, M Rosário Domingues, Pedro Domingues.

  Phospholipids are key regulators of immune metabolism, yet their specific influence on macrophage function remains incompletely defined. We investigated how phosphatidylethanolamine (PE) species with distinct acyl chains (PE18:0/22:6 and PE18:0/20:4) modulate RAW264.7 macrophages under resting and LPS-stimulated conditions using LC-MS/MS-based proteomics and metabolomics, followed by qPCR validation. LPS elicited a robust M1-like phenotype with strong upregulation of Ptgs2, Nos2, Nfkb1, and Nfkb2. PE supplementation alone did not induce a classical pro-inflammatory profile but significantly remodeled protein expression, enhancing antioxidant defenses, including catalase, Hmox1 and Prdx1. In the context of LPS activation, PE selectively attenuated inflammatory signaling by downregulating Nfkb1, Nfkb2, and Ptgs2 while further enhancing proteins linked to oxidative stress response (Prdx1 and Hmox1) and lipid metabolism (CD36 and Abcc1). qPCR corroborated these effects: both PE species reduced LPS-induced Il1b and Ptgs2 mRNA levels while increasing Prdx1, Hmox1, and Cd36 transcription. Metabolomics converged with these findings, indicating reinforced glutathione metabolism and context-dependent shifts in purine and amino-acid pathways consistent with a restrained inflammatory phenotype. Collectively, native PE species reprogram macrophage immunometabolism, mitigating LPS-driven inflammation while strengthening Nrf2-mediated antioxidant and immune-supportive pathways.

Keywords:  immunometabolism; inflammation; lipopolysaccharide; macrophages; metabolomics; oxidative stress; phosphatidylethanolamine; proteomics

DOI:  https://doi.org/10.1021/acs.jproteome.5c01131
Front Immunol. 2026 ;17 1773233

Metabolic reprogramming in tumor-associated cells of hematologic malignancies: mechanisms, crosstalk networks, and therapeutic implications in the tumor microenvironment.

Zikun Hong, Yuming Wu, Wenqi Liu, Dehu Li, Jian Xu.

  Hematologic malignancies (HMs), which originate from hematopoietic or lymphoid tissues, pose a significant therapeutic challenge due to issues such as drug resistance, relapse, and treatment-related toxicity. The tumor microenvironment (TME), especially within the bone marrow niche, is now widely recognized as a critical determinant of disease progression and treatment response. A central mechanism within this specialized niche is the extensive metabolic reprogramming of key stromal and immune cells, including tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), cancer-associated fibroblasts (CAFs), and bone marrow adipocytes (BMAds). This review systematically elaborates on the alterations in glucose, lipid, and amino acid metabolism within these cellular compartments of the HM-TME. We detail how metabolites such as lactate, fatty acids, and itaconate function not merely as metabolic byproducts but as active signaling molecules that drive critical processes like immune cell polarization, stromal remodeling, and intricate metabolic crosstalk. This comprehensive reprogramming collectively fosters a profoundly immunosuppressive milieu, promotes tumor cell survival and proliferation, and confers resistance to conventional and novel therapies. Furthermore, we explore emerging therapeutic strategies designed to target these metabolic vulnerabilities. These include inhibitors of specific metabolic pathways, modulators of metabolite-driven signaling, and innovative approaches such as nanomedicine and metabolically enhanced immunotherapy. Finally, we outline the current challenges in the field-such as intra-tumoral metabolic heterogeneity and the pressing need for targeted delivery systems-and discuss future perspectives involving advanced technologies like single-cell metabolomics and rational combination strategies. In summary, this synthesis aims to provide a comprehensive and rational foundation for developing novel immunometabolic interventions against HMs, highlighting the therapeutic potential of disrupting the metabolic dialogue within the TME.

Keywords:  amino acid metabolism; glucose metabolism; hematologic malignancies; lipid metabolism; metabolic reprogramming; tumor microenvironment; tumor-associated cells

DOI:  https://doi.org/10.3389/fimmu.2026.1773233
Int J Biol Sci. 2026 ;22(6): 2754-2773

IGF2BP2 Deficiency in Macrophages Impairs Migration, Reprograms Metabolism, and Limits Tumor Progression.

Hanna S Schymik, Selina Wrublewsky, Marcus Höring, Gerhard Liebisch, Simon Both, Gilles Gasparoni, Caroline Bickelmann, Hanah Robertson, Charlotte Dahlem, Jörn Walter, Volkhard Helms, Matthias W Laschke, Emmanuel Ampofo, Jessica Hoppstädter, Alexandra K Kiemer.

While insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) has been extensively studied in tumor cells, its role in immune cells within the tumor microenvironment, particularly in macrophages, remains largely unknown. Here, we reveal a critical function of IGF2BP2 in macrophages, demonstrating that myeloid-specific deletion of IGF2BP2 profoundly alters macrophage metabolism and polarization, and markedly impairs tumor progression. Bulk RNA sequencing of IGF2BP2 knockout (KO) macrophages revealed significant alterations in gene expression profiles, particularly impacting pathways associated with glycolysis, mitochondrial function, cell motility, and cell migration. Functional assays confirmed increased glycolytic activity and a concomitant reduction in maximal respiration and reserve respiratory capacity, indicating a metabolic shift towards glycolysis. Furthermore, IGF2BP2 deficiency impaired tumor-associated macrophage (TAM)-like polarization in vitro, as evidenced by decreased expression of TAM markers, such as Mrc1, Mmp2, and Il10. Lipidomic profiling revealed distinct lipid signatures in IGF2BP2 KO TAM-like macrophages, including alterations in triglycerides and cardiolipins, crucial for mitochondrial integrity. In vivo, deletion of IGF2BP2 specifically in the myeloid lineage was sufficient to reduce tumor growth in a subcutaneous Lewis lung carcinoma model, accompanied by decreased TAM infiltration and a shift towards a pro-inflammatory macrophage phenotype. Additionally, IGF2BP2-deficient macrophages showed impaired migratory capacity both in vitro and in vivo. These findings underscore the critical role of IGF2BP2 in controlling macrophage metabolism, polarization, and tumor-supporting functions within the tumor microenvironment, and identify myeloid IGF2BP2 as a potential therapeutic target in cancer.

DOI: https://doi.org/10.7150/ijbs.122142
Trends Cancer. 2026 Apr 09. pii: S2405-8033(26)00057-9. [Epub ahead of print]

Epigenetic, epitranscriptomic, and metabolic control of T cell exhaustion.

Chloe Slater, Albane Simon, Marguerite Laprie-Sentenac, Laurie Menger.

  T cell exhaustion is an adaptive dysfunctional state driven by chronic antigen exposure and an immunosuppressive tumor microenvironment, which significantly impedes effective antitumor immunity and T cell therapies. This progressive loss of effector function and memory potential is governed by the complex and coordinated interplay of epigenetic, transcriptional, epitranscriptomic, and metabolic networks, which collectively establish stable exhaustion-associated programs. Emerging evidence demonstrates that modulating these layers, whether permanently or transiently, can reverse exhaustion and reinvigorate T cell function. Furthermore, core metabolites serve as shared cofactors, directly linking cellular metabolism to these epigenetic and epitranscriptomic changes. Characterizing these multilayered regulatory mechanisms is critical for developing novel strategies to reprogram exhausted T cells and improve therapeutic efficacy against cancer.

Keywords:  CAR T cells; T cell exhaustion; T cell therapy; epigenetics; epitranscriptomics; metabolism

DOI:  https://doi.org/10.1016/j.trecan.2026.03.002
bioRxiv. 2026 Mar 12. pii: 2026.03.11.711168. [Epub ahead of print]

Microbial metabolism of methotrexate produces a STAT3 signaling molecule that alleviates gut inflammation.

Juyeong Cho, Rebecca Danner, Woo Sung Kim, Jonathan Williams, Anshit Singh, Jiyoung A Han, Jonathan G Van Vranken, Allison S Walker, Timothy Rhoads, Snehal N Chaudhari.

Methotrexate (MTX) therapy in inflammatory bowel disease (IBD) is often limited by inter-individual variability in clinical response and adverse effects. Gut microbiota contribute to MTX therapeutic response and toxicity by metabolizing MTX and altering its bioavailability. However, how inflammation alters microbial MTX metabolism and how its metabolites influence the host remain poorly understood. Here, we identify Clostridium asparagiforme as a potent and efficient metabolizer of methotrexate, producing deoxyaminopteroic acid (DAMPA) in the distal gastrointestinal tract. We demonstrate that DAMPA preserves mitochondrial integrity by promoting mitophagy in intestinal epithelial cells through mitochondrial STAT3 signaling. DAMPA administration attenuates intestinal inflammation in vivo , and improves metabolic dysfunction associated with IBD. Together, these findings reveal an unappreciated role for a gut microbial MTX metabolite in mediating epithelial homeostasis during intestinal inflammation, thus reframing microbial MTX metabolism from passive drug detoxification to active regulation of host mitochondrial and inflammatory homeostasis.

DOI: https://doi.org/10.64898/2026.03.11.711168
bioRxiv. 2026 Mar 12. pii: 2026.03.11.711076. [Epub ahead of print]

Metabolic reprogramming by caloric restriction enhances acute phase virological control and reduces chronic inflammation in SIV-infected rhesus macaques.

Naveen Suresh Babu, Chrysostomos Perdios, Maggie Hallmets, Anna T Brown, Celeste Coleman, Christine M Fennessey, Carolina Allers, Matilda J Moström, Pratik Khare, Cissy Zhang, Brandon T Smith, Nadia A Golden, Adam Myers, Lara Doyle-Meyers, Alexandra Blaney, Robert V Blair, Ahmad A Saied, Ricki Colman, Brandon F Keele, Anne Le, Clovis S Palmer, Joseph C Mudd.

Nutrient metabolism influences HIV-1 replication, antiviral immunity, and chronic inflammation, yet is difficult to leverage for therapeutic gain. We sought to modulate metabolism in the non-human primate model of HIV-1 by caloric restriction (CR), a modality canonically known for its antiaging benefits. Four months of 30% CR was safe and resulted in broad and systemic metabolic reprogramming in healthy adult male and female rhesus macaques. Relative to that of ad libitum- fed animals, CR lowered the frequencies of target CCR5+ CD4 T cells in the gut mucosa. Upon infection with SIV, CR reduced acute phase viremia, dampened type I interferon signaling, and overall permitted a more vigorous cycling of CD8+ T cells in lymphoid tissues. CR-induced protection from SIV was associated with a robust up-regulation of glycolysis, which supported an early reduction in viremia that ultimately waned over time. During virologic suppression with antiretroviral therapy (ART), CR significantly limited gastrointestinal (GI) immune activation, improved tricarboxylic acid cycle flux, and lowered concentrations of soluble CD14 and several TNF-related molecules in plasma. Blood SIV DNA levels however were unchanged by CR, suggesting that residual GI dysfunction and inflammation can be decoupled from viral persistence. Our findings highlight that a dietary modality can limit pathology in a primate lentiviral infection. They also reveal the robust but temporally constrained nature of glycolysis in supporting an acute antiviral response.
SIGNIFICANCE: Caloric restriction (CR) is a safe dietary intervention known to confer anti-aging and health benefits across diverse animal models. However, its application in the context of infectious diseases has yielded mixed outcomes and has largely been limited to murine systems. In this study, we therefore employed CR to examine the impact of dietary modulation on SIV infection outcomes. Our findings demonstrate that CR reduced acute-phase viremia and attenuated markers of chronic inflammation following ART, effects that were associated with distinct metabolic signatures. Collectively, these findings underscore the importance of diet and nutrition in shaping chronic viral infection outcomes, such as SIV, within a clinically relevant non-human primate model.

DOI: https://doi.org/10.64898/2026.03.11.711076
Cancer Discov. 2026 Apr 08.

Arachidonic Acid Metabolism in PMN-MDSCs Suppresses Antitumor Capacity of T cells in KRAS-Mutant Cholangiocarcinoma.

Jian Lin, Chen Sang, Bin Xiang, Xia Shen, Junmei Zhao, Shengshi Xu, Jiaomeng Pan, Youpei Lin, Liangqing Dong, Qianqian Chu, Guoming Shi, Jian Zhou, Jia Fan, Mao Zhang, Qiang Gao.

Metabolic reprogramming within the tumor microenvironment impairs antitumor immunity and compromises the efficacy of immunotherapy. Through multi-omics-based metabolic subtyping in intrahepatic cholangiocarcinoma (iCCA), we identified a subgroup with the worst prognosis that demonstrates significant enrichment in both Cyclooxygenase/Arachidonic acid (COX/AA) metabolism and KRAS mutations. Mechanistically, KRAS mutation-mediated NF-κB pathway activation upregulates CXCL5 expression, thereby recruiting CXCR2+ polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) into the tumor microenvironment. Concurrently, KRAS mutation drives prostaglandin E2 (PGE2) production in tumor cells, and PGE2 in turn enhances arachidonic acid uptake and COX-2 expression in PMN-MDSCs, establishing an amplifying loop between tumor cells and PMN-MDSCs that exacerbates PGE2 production. PGE2 accumulation potently suppresses the antitumor activity of CD8+ T cells via prostaglandin E receptor 4 (EP4). Therapeutic targeting of the COX-2-PGE2-EP4 axis, combined with anti-PD-1 immunotherapy, demonstrates profound synergistic efficacy in both KRAS-mutant murine models and patient-derived tumor fragments harboring KRAS mutations.

DOI: https://doi.org/10.1158/2159-8290.CD-25-1844
J Infect Dis. 2026 Apr 07. pii: jiag201. [Epub ahead of print]

Distinct inflammatory programming of thoracic cavity white adipose immune cells regulates influenza pathogenesis.

Cassidy J Ulanowicz, Pablo C Alarcon, Michelle S M A Damen, Jennifer L Wayland, Keisuke Sawada, John Eom, Traci E Stankiewicz, Hak Chung, Kristin Lampe, Sara Szabo, Maria E Moreno-Fernandez, Nathan Salomonis, Senad Divanovic.

   BACKGROUND: Obesity-associated inflammation in white adipose tissue (WAT) worsens outcomes of influenza A virus (IAV) infection. A recently identified thoracic cavity WAT (tcWAT) supports IAV replication. However, tcWAT's immune cell composition, functional properties and role in IAV disease severity remains unclear.
METHODS: Using a mouse model of diet-induced obesity, flow cytometry and single cell RNA-sequencing, we compared tcWAT with lung-distal visceral WAT assessing immune cell composition, transcriptomic profiles, inflammatory potential, and impact on IAV pathogenesis.
RESULTS: At baseline, tcWAT was uniquely enriched for immune cells with heightened proinflammatory capacity and exhibited a striking predominance of lymphocytic populations, including immature and Satb1+ T cells, the latter expressing gene signatures associated with elevated T cell activation. Transfer of tcWAT immune cells into IAV infected recipients accelerated IAV disease severity. IAV infection robustly reshaped tcWAT immune landscape, driving expansion of a B cell population expressing Zbtb32 and upregulating genes involved in immune regulation and antiviral responses. Concurrently, IAV infection reduced immune populations linked to neutrophil regulation in tcWAT, while these same populations were expanded in the lung.
CONCLUSIONS: These findings identify lung-proximal tcWAT as a distinct inflammatory tissue that may amplify pathogenic immune responses during IAV infection.

Keywords:  B cells; T cells; high-fat diet (HFD); inflammation; lymphocytes; obesity; white adipose tissue

DOI:  https://doi.org/10.1093/infdis/jiag201
ACS Nano. 2026 Apr 06.

Dual Energy Depletion by Zinc/Copper Disruptor to Potentiate Cuproptosis and Pyroptosis for Enhanced Tumor Immunotherapy.

Mofan Xiao, Junmin Qian, Weijun Xu, Yaping Wang, Jinlei Wang, Huichen Zhao, Xinyu Li, Lingyu Meng, Aili Suo.

  Metal ion interference therapy disrupts ion homeostasis to stimulate immunity, but the underlying mechanisms remain poorly elucidated. Here, a hydrazide hyaluronan-decorated copper/zinc disruptor is constructed to inhibit tumoral energy metabolism and activate anticancer immunity. Functionally, Zn2+ acts as a metabolic inhibitor to suppress glycolysis by directly restraining lactate dehydrogenase activity and downregulating the PI3K/Akt/HIF-1α axis, thus reducing lactate output and limiting adenosine triphosphate generation. In parallel, Cu2+ triggers cuproptosis via mitochondrial proteotoxicity and lipoylated protein aggregation, thereby blocking the flux of pyruvate into the tricarboxylic acid cycle and aggravating energy exhaustion. This metabolic collapse forms a mechanistic cascade, in which glycolytic inhibition predisposes cells to cuproptotic stress, while cuproptosis further reinforces pyroptotic activation. Ultimately, ion overload, severe energy deficit, and subsequent oxidative perturbation cooperatively amplify pyroptosis-driven inflammatory cytokine release and establish a synergistic metal ion-induced immunogenic cell death pathway. In vitro studies reveal that the anticancer activity of the disruptor involves oxidative stress, mitochondrial dysfunction, and inflammatory responses. In vivo studies demonstrate that it efficiently suppresses primary and distant tumor growth and activates systemic immunity. Collectively, this bimetallic disruption strategy bridges metal therapy with immunotherapy, provides insights into the underlying molecular mechanisms, and highlights the potential of metal-based nanomedicine for tumor immunotherapy.

Keywords:  cuproptosis; glycolysis inhibition; immunotherapy; pyroptosis; zinc/copper dual-ion disruptor

DOI:  https://doi.org/10.1021/acsnano.5c14922
Nat Metab. 2026 Apr 10.

Mitochondrial iNOS blocks itaconate production by interacting with IRG1.

Tomas Paulenda, Maxim N Artyomov.

DOI: https://doi.org/10.1038/s42255-026-01493-0
Biochem Pharmacol. 2026 Apr 07. pii: S0006-2952(26)00282-0. [Epub ahead of print] 117949

Crosstalk between cytokines and tryptophan metabolism: Therapeutic potential for immune effector cell-associated neurotoxicity syndrome.

Jianghua Wu, Dehu Li, Heng Mei, Yu Hu.

  Neuromodulation by cytokine networks plays a pivotal role in maintaining central nervous system (CNS) homeostasis. Cytokine release syndrome (CRS) and neurotoxicity are frequently and concurrently observed during chimeric antigen receptor (CAR) T cell therapy, suggesting that they are intrinsically related. Immune hyperactivation occurs after CAR-T cell infusion into human body, and the excessive secretion of cytokines results in an "overspill" into the circulation, causing multiple pathophysiological disorders, such as systemic inflammation, elevated vascular permeability and metabolic disturbance. Mounting evidence has revealed that the various pathologies of CNS are accompanied by the alterations in tryptophan metabolism. Here, we will review the advances in immune effector cell-associated neurotoxicity syndrome (ICANS) during CAR-T cell therapy, with particular focus on the crosstalk between cytokines and tryptophan metabolism for the implications for ICANS. Based on the role of tryptophan metabolism in neurological disorders, we propose a model wherein acute inflammation combines to increase brain permeability, and cytokines driven-tryptophan metabolism may subsequently synergize with host cells to trigger the occurrence of ICANS. Furthermore, we discuss the potential of crosstalk between cytokines and tryptophan metabolism as therapeutic targets in clinical applications to provide insight into possible therapeutic strategies for ICANS.

Keywords:  CAR-T cell; Cytokines; ICANS; Tryptophan metabolism

DOI:  https://doi.org/10.1016/j.bcp.2026.117949
Cell Biochem Funct. 2026 Apr;44(4): e70211

High Glucose Triggers Macrophage Senescence Through Mitochondrial Dysfunction and Mitophagy Impairment.

Liying Tang, Xiuting Huang, Pei Li.

  Chronic hyperglycemia accelerates immune aging and contributes to diabetic complications, yet the mitochondrial mechanisms responsible for macrophage senescence remain unclear. In this study, both cultured and primary macrophages were treated with high glucose to model hyperglycemic conditions. High glucose significantly increased markers of macrophage senescence, including SA-β-Gal staining, expression of p16 and p21, and secretion of pro-inflammatory cytokines. Mitochondrial dysfunction was evident, as shown by loss of mitochondrial membrane potential (ΔΨm) and elevated mitochondrial reactive oxygen species (mtROS). In addition, mitophagy was impaired, with PINK1 accumulation and reduced Parkin recruitment. Rescue experiments demonstrated that treatment with the mitochondria-targeted antioxidant MitoTempo, the general antioxidant N-acetylcysteine, or the anti-diabetic drug metformin effectively restored mitochondrial function and alleviated senescence. These findings indicate that mitochondrial dysfunction and impaired mitophagy are central to high glucose-induced macrophage senescence, and that targeting mitochondrial oxidative stress with antioxidants or metformin may offer a promising strategy to mitigate immune aging and inflammation associated with metabolic disorders.

Keywords:  high glucose; inflammation; macrophage; mitophagy; senescence

DOI:  https://doi.org/10.1002/cbf.70211
bioRxiv. 2026 Mar 10. pii: 2026.03.09.710628. [Epub ahead of print]

Epstein-Barr Virus Latent Membrane Protein 1 Suppresses Ferroptosis via Pentose Phosphate Pathway and Glutathione Metabolism.

Eric M Burton, Bidisha Mitra, Rui Guo, John M Asara, Benjamin E Gewurz.

Epstein-Barr virus (EBV) is associated with 200,000 cancers per year, including Burkitt lymphoma and post-transplant lymphomas. We previously reported that EBV latency oncogene programs dynamically remodel infected B cell metabolism and sensitivity to induction of ferroptosis, a programmed cell death pathway driven by lipid reactive oxygen species. However, much has remained unknown about how EBV remodels key redox defense pathways in support of infected B cell proliferation. Here, we identify EBV latent membrane protein 1 (LMP1), a key viral oncogene necessary for B cell immortalization and which mimics aspects of CD40 signaling, drives resistance to ferroptosis induction by erastin, a small molecule that blocks cystine uptake. LMP1 expression was sufficient to protect Burkitt cells from erastin ferroptosis induction. Mechanistically, signaling from the LMP1 TES2/CTAR2 region drove this phenotype, which was not shared by CD40 signaling, revealing that LMP1 evolved independent redox defense roles. Metabolomic analysis highlighted key LMP1 and TES2 signaling roles in support of antioxidant cysteine and glutathione levels. TES2 signaling supported cystine uptake, glutathione and NADPH pools in newly infected peripheral blood B cells. We identified PFKFB4, a host enzyme that shunts glucose into the pentose phosphate pathway to support NADPH production, as a major TES2 metabolic target. PFKFB4 knockdown increased EBV-transformed lymphoblastoid cell line lipid ROS levels, decreased glutathione and strongly sensitized them to ferroptosis induction by erastin treatment. PFKFB4 was also necessary for LMP1-mediated Burkitt B cell ferroptosis resistance. Collectively, these results identify PFKFB4 as a key host cell EBV metabolism remodeling target critical for infected B cell redox defense.

DOI: https://doi.org/10.64898/2026.03.09.710628
Clin Epigenetics. 2026 Apr 10.

Hexokinase 3 promoted cytokine production of monocytes by targeting metabolic reprogramming and histone lactylation in sepsis.

Cuiying Lian, Qizhong Xu, Hongjian Shi, Yuxuan Xie, Jianwei Fang, Boqi Rao, Tianxing Ji, Huilin Jiang, Zhuowen Wu, Xiao-Hui Chen, Shao-Peng Lin.

  Sepsis is a life-threatening organ dysfunction caused by a dysregulated host immune response to infection, and there is currently a lack of early rapid identification and effective treatment methods. During the pathogenesis of sepsis, immune cells such as monocytes exhibit abnormal activation of aerobic glycolysis. However, the mechanism of glycolysis in immune cells during sepsis remains to be elucidated. Here, we investigated the role of glycolysis-related regulatory genes in the development of sepsis. Through analysis of the GEO database, we found that HK3 is significantly elevated in the peripheral blood of sepsis patients. Receiver operating characteristic (ROC) curve analysis demonstrated that HK3, as a novel metabolic checkpoint, serves as an excellent diagnostic biomarker for sepsis. Immune cell infiltration analysis revealed a significant increase in monocyte infiltration in the peripheral blood of sepsis patients. Single-cell RNA sequencing analysis demonstrated a significant increase in HK3 expression in monocytes from the sepsis group compared to the control group. Using an LPS-induced monocyte sepsis model, we found that HK3 boosts glycolytic activity and lactate accumulation. Mechanistically, this enhances inflammatory cytokine secretion through H3K18 lactylation-dependent activation of IL-6 and TNF-α genes. Notably, targeted HK3 knockdown effectively suppressed this pro-inflammatory cascade, highlighting its critical role in sepsis pathogenesis. Our findings not only establish HK3 as a key metabolic regulator in sepsis but also elucidate its molecular mechanism in driving excessive monocyte-mediated inflammation. Moreover, we identify HK3 as a promising therapeutic target for mitigating hyperinflammatory responses in sepsis.

Keywords:  Glycolysis; Hexokinase; Histone; Lactylation; Monocyte; Sepsis

DOI:  https://doi.org/10.1186/s13148-026-02129-6
iScience. 2026 Apr 17. 29(4): 115372

Targeting KIF20A blocks lactylation modification to suppress immune escape in hepatocellular carcinoma.

Shujia Chen, Lili Zhao, Tongguo Miao, Ping Han, Jie Liu, Jiancun Hou, Qiang Zhao, Fengmei Wang, Jia Li.

  Hepatocellular carcinoma (HCC) evades anti-PD-1 immunotherapy via an immunosuppressive microenvironment, where lactate links metabolic reprogramming to epigenetic regulation. We analyzed pan-lysine lactylation and H3K18 lactylation (H3K18la) in 89 HCC patient pairs, and validated functional mechanisms using glycolysis inhibition, HCC-CD8+ T cell co-cultures, and rescue assays. In vivo efficacy was assessed in subcutaneous and orthotopic HCC mouse models. H3K18la levels were elevated in HCC, correlating with advanced staging and poor prognosis. Lactate induced H3K18la to transcriptionally upregulate KIF20A, which stabilized the c-Myc/PD-L1 axis and suppressed cytotoxic T cell function. Combined glycolysis inhibition and anti-PD-1 therapy reversed this immunosuppression and synergistically inhibited tumor growth. This study identifies an H3K18la-KIF20A/PD-L1 axis as a key metabolic-epigenetic checkpoint, highlighting glycolysis targeting as a promising strategy to enhance anti-PD-1 responses in HCC.

Keywords:  health sciences; hepatology; internal medicine; medical specialty; medicine

DOI:  https://doi.org/10.1016/j.isci.2026.115372
Cell Death Dis. 2026 Apr 08.

ARID1A deficiency-driven reprogramming of polyamine metabolism promotes endometrial cancer malignancy and immune escape.

Han Tao, Xiaojun Wang, Zhiyi Hu, Yiran Li, Mengwen Kong, Yeli Sun, Kun Gao, Xiaoping Wan.

Metabolic reprogramming is crucial in developing endometrial cancer (EC); however, the mechanisms through which tumor suppressors control metabolites that drive cell proliferation and tumor growth remain unclear. ARID1A, an SWI/SNF chromatin remodeling complex subunit, is frequently mutated in endometrium-related malignancies. Here, EC tumors with ARID1A deleted exhibit increased polyamine production, which enhances malignant proliferative capacity while inhibiting the efficacy of functional CD8+ T cells. Mechanistically, ARID1A depletion in tumor cells interrupts the competitive binding of ARID1A to YAP, causing excessive YAP activation and transcriptionally increasing the expression of polyamine metabolic enzymes, thereby enhancing polyamine synthesis. Increased spermidine production from polyamines can directly hypusinate eukaryotic translation initiation factor 5A (eIF5A) at lysine residues, resulting in efficient histone demethylase LSD1 protein translation. Moreover, polyamine accumulation suppresses the recruitment of CD8+ T cells and hampers antitumor immune responses in vivo. Notably, polyamine depletion induced by eflornithine (DFMO) significantly reduces EC cell proliferative capacity and enhances CD8+ T-cell efficacy. Together, these findings highlight the role of ARID1A in regulating polyamine metabolism and suggest that elevated polyamine levels in tumors enhance malignant cellular behaviors and contribute to immune evasion by inhibiting CD8+ T cell-mediated cytotoxic responses. Therefore, targeting polyamine biosynthesis could be an important therapeutic strategy for ARID1A-inactivated EC.

DOI: https://doi.org/10.1038/s41419-026-08722-0
Nat Commun. 2026 Apr 08.

Chitinase-like proteins de-N-glycosylating CD36 modify cholesterol metabolism in atherosclerotic macrophages.

Yu Wang, Jing Zhang, Meiyang Fan, Xianbin Hou, Xiaomeng Li, Wentao Zhang, Wenbin Liu, Yue Li, Yaqi Lu, Fei Li, Yanglong Guan, Yudan Wang, Bingyu Yuan, Xiaowei Li, Huilin Gong, Feng Ning, Xiaozhen Zhuo, Shemin Lu, Liesu Meng, Rikard Holmdahl, Wenhua Zhu.

Polymorphisms of mouse chitinase-like protein 3 (Chil3), a member of the mammalian chitinase-like protein (CLP) family, have been demonstrated to be associated with inflammatory diseases by regulating lipid metabolism. However, the specific immunomodulatory impacts of CLPs, mainly mouse CHIL3 and its human functional homologue chitinase-3-like 2 (CHI3L2), on macrophage cholesterol metabolism and atherosclerosis have remained unclear. Here, we find CLPs (CHIL3 and CHI3L2) accelerate atherogenesis in a macrophage-dependent manner. Mechanistically, we identify an autocrine mechanism through which CLPs regulate cholesterol metabolism in macrophages. Macrophage-secreted CLPs exacerbate lipid uptake by binding to CD36. CLPs exhibit glycosidase activity, targeting and hydrolyzing N-glycosylated glycans on CD36, predominantly at sites N220 and N321, thereby enhancing lipid uptake. Increased lipid influx activates mTOR in macrophages, driving their transition to a pro-inflammatory phenotype while simultaneously suppressing peroxisome proliferator-activated receptor gamma (PPARγ) expression and thus impairing ABCG1-mediated cholesterol efflux. Single-cell sequencing reveals that CLPs increase atherosclerotic foamy macrophages, favoring vascular smooth muscle cells (VSMC) transformation into foam and osteoblast-like cells. Additionally, neutralizing antibodies targeting CHI3L2 prevent and treat atherosclerosis. These findings highlight the potential of CLPs as targets for disease diagnosis and therapy.

DOI: https://doi.org/10.1038/s41467-026-71388-x
Endocr Metab Immune Disord Drug Targets. 2026 Apr 03.

Uncovering Mediating Mechanisms Linking Immune Cells to Systemic Lupus Erythematosus: Insights into Mendelian Randomization.

Zenghui Liu, Lu Kuang, Jiaxing Zhao, Huayu Yin, Xuehui Liu, Dabin Liu, Shaoguo Wu, Limei Wu.

   INTRODUCTION: Systemic lupus erythematosus (SLE) involves dysregulated immune cell function, though its exact pathogenic mechanisms remain unclear.
METHODS: We performed a two-sample Mendelian randomization (MR) study using extensive GWAS summary statistics, covering 731 immune cell phenotypes, 91 inflammatory proteins, 179 lipid types, 1,400 blood metabolites, and SLE cases. The analysis aimed to evaluate causal associations between these variables and SLE. Additionally, we investigated possible mediating roles of inflammatory proteins, blood lipids, and metabolites through mediation analysis, with various sensitivity tests confirming the reliability of our findings.
RESULTS: We identified 20 immune cell phenotypes, 3 inflammatory proteins, 3 lipid types, and 17 blood metabolites with significant causal associations with SLE. Mediation analysis revealed that the protective effect of CCR2 on CD62L+ myeloid DCs against SLE was partly mediated by phosphatidylcholine (O-18:1_20:4) (12%) and sterol ester (27:1/20:3) (10.4%). Moreover, sphingomyelin (d18:1/20:0, d16:1/22:0) accounted for 14.7% of the protective effect of CD28 on CD45RA- CD4+ cells, not Treg, against SLE.
DISCUSSION: These findings enhance our understanding of disease pathogenesis, indicating that modulating key metabolic pathways and immune regulatory nodes could represent promising therapeutic approaches. However, additional experimental studies are needed to validate these potential causal relationships.
CONCLUSION: Using causal inference approaches, our study identifies immune cell-mediated mechanisms underlying SLE pathogenesis, involving inflammatory proteins, lipids, and metabolites. These findings suggest potential intervention pathways for further mechanistic exploration and therapeutic development.

Keywords:  Immune cells; inflammatory proteins; mendelian randomization.; plasma lipidome; plasma metabolites; systemic lupus erythematosus

DOI:  https://doi.org/10.2174/0118715303407042251210161902
Cancer Biol Med. 2026 Apr 02. pii: j.issn.2095-3941.2026.0110. [Epub ahead of print]

Lactate drives immune resistance via a pharmaceutically reversible H3K18la-KIF20A-c-Myc-PD-L1 axis in hepatocellular carcinoma.

Shujia Chen, Lili Zhao, Ping Han, Jie Liu, Jiancun Hou, Xiaomei Liu, Qiang Zhao, Rongqi Wang, Fengmei Wang, Jia Li.

   OBJECTIVE: Resistance to immunotherapy, driven by the immunosuppressive tumor microenvironment, remains a major clinical challenge in hepatocellular carcinoma (HCC). Although metabolic reprogramming is a known culprit, the precise epigenetic mechanisms linking lactate accumulation to immune evasion are poorly defined.
METHODS: Immunohistochemistry analysis of 89 pairs of HCC and paracancerous tissues was conducted to correlate histone h3 lysine 18 lactylation (H3K18la) levels with TNM stage. A separate clinical cohort of 46 patients with HCC was enrolled to assess the association between H3K18la levels and anti-PD-1 therapy resistance. Chromatin immunoprecipitation sequencing in HCC cells, performed to screen for downstream targets, identified kinesin family member 20A (KIF20A). The regulatory relationships among H3K18la, KIF20A, c-Myc, and PD-L1 were verified with dual-luciferase reporter assays and chromatin immunoprecipitation-PCR. The immune evasion mechanism was explored through gene knockdown/overexpression in HCC cells, followed by co-culture with CD8+ T cells and functional analysis via flow cytometry. Finally, a subcutaneous mouse xenograft model was established to evaluate the synergistic efficacy of a glycolysis inhibitor combined with anti-PD-1 therapy on tumor growth and the tumor immune microenvironment.
RESULTS: Histone lactylation (forming H3K18la) was identified as a key epigenetic checkpoint linking tumor metabolism to immunotherapy failure in HCC. Elevated H3K18la is a reliable biomarker for tumor progression and resistance to anti-PD-1 therapy. Mechanistically, we discovered that lactate-driven H3K18la directly activates transcription of the oncogene KIF20A. KIF20A in turn stabilizes c-Myc protein, thereby enhancing PD-L1 expression and attenuating anti-tumor immunity. This immunosuppressive phenotype was therapeutically reversible: genetic silencing of KIF20A restored T cell function, and pharmacological inhibition of glycolysis acted synergistically with anti-PD-1 therapy in suppressing tumor growth and extending survival by dismantling the H3K18la-KIF20A axis.
CONCLUSIONS: This study deciphered a novel druggable metabolic-epigenetic pathway (lactate-H3K18la-KIF20A-Myc-PD-L1) responsible for immune evasion in HCC. Targeting this axis might offer a promising strategy to reprogram the tumor microenvironment and restore immunotherapy sensitivity.

Keywords:  H3K18 lactylation; Hepatocellular carcinoma; PD-L1; c-Myc; immunotherapy resistance; kinesin family member 20A

DOI:  https://doi.org/10.20892/j.issn.2095-3941.2026.0110
Front Clin Diabetes Healthc. 2026 ;7 1791782

Linking inflammation, metabolic dysfunction, and neurodegeneration: a comprehensive review of TLR2 pathways in type 2 diabetes.

Juan Antonio Arreguín-Cano, Sandra Aidé Santana-Delgado, Carlos Esteban Villegas-Mercado, Grissel Guadalupe Orozco-Molina, Adolfo González-Acosta, Mercedes Bermúdez.

  Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder increasingly recognized as a systemic inflammatory condition with significant neurological effects. Growing evidence shows that chronic low-grade inflammation (CLGI), insulin resistance, and metabolic imbalance contribute to cognitive decline and the development of neurodegenerative diseases like Alzheimer's and Parkinson's. Toll-like receptor 2 (TLR2), a critical pattern-recognition receptor of the innate immune system, has emerged as an essential molecular link between metabolic dysfunction and neuroinflammation and neuronal damage. This review summarizes current experimental, clinical, and translational evidence on the role of TLR2 in T2DM-related inflammation, mitochondrial dysfunction, lipid imbalance, insulin resistance, and blood-brain barrier (BBB) issues. We explore how ongoing TLR2 activation by internal danger signals and metabolic stressors maintains systemic inflammation and fuels neuroimmune responses via microglial activation and cytokine release, thereby accelerating neurodegenerative processes. Additionally, we discuss new therapeutic strategies targeting TLR2 signaling, including drugs, dietary supplements, and the repurposing of antidiabetic medications with neuroprotective effects. By combining immunometabolic and neurodegenerative pathways, this review highlights TLR2 as a promising target for preventing or reducing diabetes-related cognitive decline neurodegeneration.

Keywords:  chronic low-grade inflammation; immunometabolism; insulin resistance; neurodegeneration; neuroinflammation; toll-like receptor 2 (TLR2); type 2 diabetes mellitus (T2DM)

DOI:  https://doi.org/10.3389/fcdhc.2026.1791782
Cell Mol Immunol. 2026 Apr 07.

Lipid metabolism reprogramming shapes the immune landscape in the tumor microenvironment.

Yun-Wei Du, Ze-Rong Cai, Xiao-Tong Duan, Xin-Yu Li, Tong Yue, Tian Tian, Jian-Jun Li, Huai-Qiang Ju.

  Given the fundamental biological importance of lipids not only as structural components and energy substrates but also as potent bioactive molecules that govern immune and oncogenic signaling, lipid metabolism reprogramming has emerged as a central driver of tumor progression. Rather than merely fueling tumor growth, this extensive metabolic rewiring profoundly reshapes the tumor microenvironment (TME), establishing complex metabolic crosstalk that actively drives immune evasion. This review examines the current understanding of lipid metabolism reprogramming across different cellular compartments within the TME and its far-reaching implications for cancer immunotherapy. We first delineate how altered lipid metabolism directly fuels tumor cell proliferation, survival, and metastatic potential. We then examine the distinct lipid metabolic patterns in different immune cells, detailing how this reprogramming drives dysfunction in antitumor subsets such as CD8+ T cells and natural killer cells and how it promotes immunosuppressive populations such as tumor-associated macrophages and myeloid-derived suppressor cells. In addition to these immune alterations, we address the metabolic rewiring of stromal cells, particularly cancer-associated fibroblasts. Furthermore, by exploring intricate intercellular crosstalk, we highlight how tumor lipid metabolism promotes immune escape and how lipids from reprogrammed immune and stromal cells, in turn, support tumor growth, thereby reinforcing an immunosuppressive niche. Finally, we highlight emerging therapeutic strategies targeting these pathways and discuss how leveraging multiomics advances can translate lipid insights into cancer immunotherapy.

Keywords:  Lipid metabolism reprogramming; antitumor immunity; immune evasion; tumor microenvironment

DOI:  https://doi.org/10.1038/s41423-026-01411-0
bioRxiv. 2026 Apr 01. pii: 2026.03.30.715168. [Epub ahead of print]

FNIP1 Modulates B Cell Receptor Signaling Strength by Coordinating Metabolism During Development.

Heon Park, Ryan Culbert, Dechen Sakya, Raynah R Silprasert, Brian M Iritani.

B cell development relies on stringent checkpoints that ensure immune competence and eliminate autoreactive clones. Transitional B cells (B220⁺CD93⁺), which emerge from the bone marrow, migrate to the spleen and differentiate into follicular (FO) or marginal zone (MZ) B cells, a process governed by B cell receptor (BCR) signaling strength, metabolic fitness, and survival cues. Here, we identify Folliculin Interacting Protein 1 (Fnip1) as a key regulator of this developmental transition. Using conditional Fnip1-deficient mice ( Fnip1 fl/fl CD21Cre ), loss of Fnip1 results in a developmental arrest at the transitional B220⁺CD93 mid stage, severely limiting differentiation into FO and MZ B cells and leading to accumulation of a distinct enlarged CD19 high , RAG negative B cells. Fnip1 modulates BCR signaling thresholds and metabolic programming by regulating the AMPK/FLCN/TFEB and CD19/PI3K/Akt/mTORC1 pathways through restricting TFEB access to the nucleus. Using the MD4/mHEL/sHEL tolerance model, we show that Fnip1 is dispensable for negative selection but is essential for maintaining peripheral tolerance. Together, our findings define Fnip1 as a metabolic gatekeeper that integrates nutrient-sensing pathways with BCR signaling to orchestrate transitional B cell fate decisions, promote peripheral tolerance, and maintain immune homeostasis.

DOI: https://doi.org/10.64898/2026.03.30.715168
Front Immunol. 2026 ;17 1766322

Aberrant long-chain fatty acids metabolism and its interplay with immuno-inflammatory responses in relapsing-remitting multiple sclerosis.

Xiao-Xi Zhu, Pei-Juan Wang, He-Xu Liu, Peng Sun, Li-Mei Yu, Fan Yang.

   Background: Growing evidence indicates significant alterations in fatty acid metabolism in patients with relapsing-remitting multiple sclerosis (RRMS). However, the metabolic status of long-chain fatty acids (LCFAs), including mono-unsaturated fatty acids (MUFAs) and poly-unsaturated fatty acids (PUFAs), and their potential link to immune-inflammatory responses during RRMS relapses, remain unclear. This study aims to uncover the aberrant metabolic signatures of LCFAs, potential LCFA biomarkers during RRMS relapses, and their interactive network with peripheral inflammatory responses.
Methods: In this study, plasma samples from 20 RRMS patients and 22 age- and sex-matched healthy controls (HCs) were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based untargeted metabolomics method.
Results: Metabolomics analysis revealed marked changes in the LCFA metabolic profile of RRMS patients. Compared to HCs, 26 differentially abundant metabolites (DAMs) belonging to amino acids, fatty acids, and their derivatives were identified in RRMS samples, including significantly upregulated LCFA palmitic acid (FA 16:0) (Padj < 0.001), MUFA oleic acid (FA 18:1) (Padj < 0.05), PUFA arachidonic acid (FA 20:4) (Padj < 0.01), and significantly downregulated dodecanoic acid (FA 12:0) (Padj < 0.01). These DAMs were mainly enriched in amino acid, fatty acid, and lipid synthesis/metabolism pathways. Additionally, the circulating levels of pro-inflammatory factors TNF-α and IL17A were significantly elevated (Padj < 0.001), while the concentrations of chemokines such as IL1RA, CCL2, CCL3, CCL4, CCL5, PDGFB, IL7, CXCL8, IL9, and IL12A were significantly reduced (Padj < 0.01) in RRMS compared to HC samples. Linear regression analysis showed significant positive correlations between FA 20:4 and IL17A (r = 0.370, Padj < 0.05), and significant negative correlations between FA 16:0 and PDGFB (r = -0.339, Padj < 0.05). Receiver operating characteristic (ROC) curve analysis indicated that individual fatty acids (e.g., FA 12:0 [AUC = 0.881], FA 18:1 [AUC = 0.833], FA 16:0 [AUC = 0.881]) have high potential for predicting RRMS, with higher accuracy, specificity, and sensitivity when combining two (FA 12:0 and FA 18:1 [AUC = 0.929]) or four (FA 12:0, FA 18:1, FA 16:0, and FA 20:4 [AUC = 0.952]) fatty acids.
Conclusion: Our results uncover the aberrant metabolic features of LCFAs and potential biomarkers in RRMS patients, and the interactive network and key molecular nodes between LCFAs and peripheral immune-inflammatory responses. The interplay between LCFAs and immuno-inflammation may drive the migration of inflammatory events from the periphery to the CNS, reigniting CNS neuroinflammation and causing RRMS relapses. These findings offer valuable insights for RRMS diagnosis and novel therapeutic development.

Keywords:  chemokine; cytokine; immune-metabolic network; inflammation; long-chain fatty acid; mono-unsaturated fatty acid; poly-unsaturated fatty acid; relapsing-remitting multiple sclerosis

DOI:  https://doi.org/10.3389/fimmu.2026.1766322
J Cereb Blood Flow Metab. 2026 Apr 04. 271678X261437569

Exploring brain glucose metabolism in multiple sclerosis: A deuterium metabolic imaging study.

Alixander S Khan, Kamilla Kørup Trosborg, Michael Vaeggemose, Tobias Gaemelke, Esben S S Hansen, Nichlas Vous Christensen, Jack J Miller, Rolf F Schulte, Caroline Winther Tørring, Ulrik Dalgas, Lars G Hvid, Christoffer Laustsen.

  Axonal demyelination is a key feature in multiple sclerosis (MS), that is, increasingly linked to a state of energetic failure, however current non-invasive methods to probe downstream metabolic changes are lacking. This study aimed to investigate Deuterium Metabolic Imaging (DMI) to measure alterations in glucose metabolism in MS compared to healthy controls (HC). In this prospective study DMI was performed on eight patients with relapsing-remitting MS (RRMS) together with eight age- and sex-matched HC. Following oral administration of [6,6'-2H2] glucose, DMI was acquired on 3 T MRI to quantify the metabolic conversion of glucose (Glc) into glutamate and glutamine (Glx) and lactate. White matter (WM) oxidative metabolism (2H-Glx/2H-Water), showed a negative correlation with the Expanded Disability Status Scale score (EDSS) (Pearson r = -0.71, p = 0.049). Glucose (2H-Glc/2H-Water), remained unchanged across EDSS (Pearson r = -0.13, p = 0.76). Impaired glucose levels and oxidative metabolism in WM correlated negatively with increased number of T2-FLAIR lesions (Pearson r = -0.86 to -0.83, respectively). These in vivo findings provide evidence for a relative failure of oxidative energy production within the WM of RRMS compared to HC offering proof of concept that DMI is a feasible tool for measuring neurodegeneration related metabolic changes.

Keywords:  MR spectroscopy; MRI; Metabolism; X-nuclei; multiple sclerosis

DOI:  https://doi.org/10.1177/0271678X261437569
JCI Insight. 2026 Apr 08. pii: e197470. [Epub ahead of print]11(7):

Vancomycin eliminates gut deoxycholic acid, restoring ER proteostasis in ILC2s and relieving colitis.

Qiuheng Tian, Han Liu, Xiang Gu, Jing Shen, Xi Yuan, Mengqi Zheng, Yunjiao Zhai, Yatai Chen, Penghu Han, Yangchun Ma, Wei Xin, Hongyue Ma, Yu Li, Sihan Wang, Lei Guo, Detian Yuan, Yanbo Yu, Shiyang Li.

  Ulcerative colitis (UC) remission is marked by gut microbiota restructuring, but how microbial metabolites influence immune-mediated tissue repair is unclear. Here, we demonstrate that oral vancomycin alleviates colitis symptoms in murine models, mirroring its clinical efficacy in inducing remission in patients with UC. Mechanistically, vancomycin's therapeutic effect is achieved by reducing deoxycholic acid (DCA). We reveal that DCA impairs mucosal repair driven by group 2 innate lymphoid cells (ILC2s) by inducing ER stress through direct binding to thioredoxin-related transmembrane protein 2 (TMX2). This interaction disrupts TMX2's role in protein folding, triggering unresolved unfolded protein response via hyperactivation of PERK/eIF2α signaling, which suppresses the production of pro-healing molecules by ILC2s. Pharmacological inhibition of PERK phosphorylation restores ILC2 function and accelerates colitis resolution. Our work uncovers a pathogenic microbiota/DCA/ILC2 axis that obstructs mucosal healing and positions vancomycin as a targeted strategy to eliminate DCA, thereby promoting UC remission.

Keywords:  Gastroenterology; Immunology; Inflammatory bowel disease; Innate immunity; Protein misfolding

DOI:  https://doi.org/10.1172/jci.insight.197470
BMC Genomics. 2026 Apr 06.

Integrated transcriptomics, proteomics, and metabolomics analysis reveals newcastle disease virus reshapes glycerophospholipid metabolism.

Yifan Sun, Tian Fang, Lei Tan, Cuiping Song, Xusheng Qiu, Ying Liao, Yingjie Sun, Xiufan Liu, Chan Ding, Chunchun Meng.



Keywords:  Newcastle disease virus; glycerophospholipid metabolism; metabolomics; proteomics; transcriptomics

DOI:  https://doi.org/10.1186/s12864-026-12760-5
Front Immunol. 2026 ;17 1793631

Peptide hydrogel boosts the cytotoxic and metabolic fitness of Vγ9Vδ2 T cells in melanoma immunotherapy.

Hongjie Liu, Man Li, Ying Jiao, Lilumeng Huang, Qi Liu, Shuang Xiao, Mingjie Zhan, Xianfeng Zha, Li Shi, Zhinan Yin, Zheng Xiang, Chengbiao Yang, Yan Xu.

   Background: Adoptive cell therapy with Vγ9Vδ2 T cells represents a promising approach for melanoma treatment. However, its efficacy is often limited by poor persistence, inadequate tumor infiltration, and functional suppression within the tumor microenvironment. Peptide-based hydrogel as a vehicle has exhibited great potential for delivery of biologics and enhancement of their function, but their ability to directly modulate the metabolic and cytotoxic fitness of Vγ9Vδ2 T cells remains largely unexplored.
Methods: We developed a peptide hydrogel (Self-assembly material based on peptide Nap-GFFF, named as SAM.1) and assessed its ability to activate Vγ9Vδ2 T-cell and amplify their cytotoxicity to A375 melanoma cells in vitro, and to enhance antitumor efficacy in a melanoma xenograft model. Mechanistic studies focused on integrin signaling, PI3K/AKT/mTOR activation, and metabolic reprogramming.
Results: SAM.1 significantly enhanced the cytotoxic activity of Vγ9Vδ2 T cells against A375 melanoma cells in vitro. It promoted Vγ9Vδ2-T cell activation, evidenced by increased CD25 and CD69 expression, and boosted the secretion of key cytotoxic effector molecules such as IFN-γ, TNF-α and perforin. Mechanistically, SAM.1 engaged integrin signaling (upregulating CD11c and CD103), leading to activation of the PI3K/AKT/mTOR pathway. This signaling cascade drove a beneficial metabolic reprogramming, shifting T cell energy production from glycolysis towards oxidative phosphorylation, thereby enhancing their bioenergetic capacity. Beyond that, peritumoral delivery of Vγ9Vδ2 T cells increased intratumoral T cell infiltration. As a result, melanoma growth was inhibited after administration of SAM.1 encapsulating Vγ9Vδ2 T cells.
Conclusion: SAM.1 hydrogel acted as a two-in-one scaffold, controlled release and an immunomodulatory agent, to enhance the persistence and antitumor function of Vγ9Vδ2 T cells. This strategy provided a new paradigm for γδ T-cell-based immunotherapy in melanoma.

Keywords:  Vγ9Vδ2 T cells; immunotherapy; integrin signaling; melanoma; metabolic reprogramming; peptide hydrogel

DOI:  https://doi.org/10.3389/fimmu.2026.1793631
Sci Adv. 2026 Apr 10. 12(15): eadz9095

RNA binding protein Pcbp1 maintains mitochondria integrity to promote antibody production and germinal center response.

Lizhen Zhu, Li Lin, Tuan Qi, Geng Li, Zhixing Liang, Jiancheng Yu, Yifan Fu, Yue Peng, Xing Chang.

B cells are crucial for adaptive immunity, orchestrating humoral responses by producing antibodies essential for pathogen clearance. Here, we show that Poly(rC) binding protein 1 (Pcbp1), a multifunctional RNA binding protein, is a key regulator of antibody production in B cells. Pcbp1 deficiency in B cells resulted in significant reductions in immunoglobulin M expression at steady state and compromised differentiation of germinal center B cells and production of high-affinity antibodies upon immunization. These effects were caused by defective mitochondrial integrity in Pcbp1-deficient B cells, including impaired mitochondrial electron transport chain complex I and elevated mitochondrial reactive oxygen species production. Mechanistically, Pcbp1 binds to the 3' untranslated region of Fdxr messenger RNA to promote its expression, thereby supporting iron-sulfur cluster biogenesis, the assembly of mitochondrial complex I, and other Fdxr-dependent processes. Our findings reveal a previously unidentified role for Pcbp1 in regulating mitochondrial function, protein synthesis, and antibody responses in B cells, providing insight into posttranscriptional regulation and mitochondrial functions in adaptive immunity.

DOI: https://doi.org/10.1126/sciadv.adz9095
Cell Mol Gastroenterol Hepatol. 2026 Apr 07. pii: S2352-345X(26)00060-3. [Epub ahead of print] 101782

IL-13 promotes accumulation of esophageal epithelial mitochondria with translational implications for eosinophilic esophagitis.

Jazmyne L Jackson, Reshu Saxena, Mary Grace Murray, Abigail J Staub, Courtney Worrell, Jasmine Cruz, No'ad Shanas, Alena Klochkova, Travis H Bordner, John M Crespo, Annie D Fuller, B S William-Nazario-Lugo, Grace Davis, Hailey Golden, Andres J Klein-Szanto, Tatiana A Karakasheva, Adam Karami, John W Elrod, Gary W Falk, Zachary Wilmer Reichenbach, Melanie Ruffner, Amanda B Muir, Kelly A Whelan.

   BACKGROUND & AIMS: Metabolic and mitochondrial dysfunction have recently been implicated in eosinophilic esophagitis (EoE) pathogenesis. However, there is a need to define the influence of EoE-associated inflammatory cues upon mitochondrial biology, mechanisms mediating these effects, and the clinical significance of mitochondrial alterations in EoE.
METHODS: Mitochondria were evaluated in human biopsies, MC903/Ovalbumin-induced murine EoE, and human esophageal keratinocytes stimulated with EoE-relevant cytokines. Mitochondrial mediators were assessed via qRT-PCR and western blotting. Metabolism, mitochondrial membrane potential, and apoptosis were measured. Mitochondrial DNA (mtDNA)-encoded genes, ND1 and ND6 were assessed by qPCR in DNA from culture media and circulating nucleic acids from human serum samples. Effects of JAK inhibitor ruxolitinib or genetic inhibition of STAT3 or STAT6 on mitochondria were assessed in vitro.
RESULTS: We identified evidence of increased mitochondria in esophageal mucosa of EoE patients and mice with EoE-like inflammation. IL-13 consistently induced mitochondrial accumulation in esophageal keratinocytes in vitro and this response was associated with increased expression of mediators of mitochondrial biogenesis, fusion, and mitophagy. IL-13 suppressed mitochondrial respiration and ATP production, without impacting membrane polarization or apoptosis. Active EoE patients exhibited elevated serum mtDNA levels and upregulation of mediators of mtDNA-associated inflammatory signaling. Increased mitochondrial mass and accumulation of extracellular mtDNA in IL-13-treated esophageal keratinocytes were dependent on JAK/STAT signaling.
CONCLUSIONS: We identify IL-13 as a mediator of increased mitochondrial mass in EoE through JAK/STAT signaling. We further demonstrate that IL-13 promotes accumulation of extracellular mtDNA and that circulating mtDNA is elevated in EoE patients.

Keywords:  Eosinophilic esophagitis; Interleukin-13; JAK/STAT pathway; mitochondria

DOI:  https://doi.org/10.1016/j.jcmgh.2026.101782