bims-imicid 2026-08-23 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2026–08–23
twenty-six papers selected by
Dylan Gerard Ryan, Trinity College Dublin

Evolution and Mechanistic Insights of Immunometabolism in Metabolic Diseases and Infections.
SAMHD1 enhances HIV-1-induced glycolysis in monocytic cells through hexokinase 2 upregulation.
Distinct spatiotemporal immunometabolic remodeling following acute traumatic brain injury.
A lactate-α-ketoglutarate metabolic circuit in tumor-infiltrating regulatory T cells accelerates tumor progression by inducing NK cell senescence.
Mitochondrial profiling across macrophage states reveals inhibition of IL-4/IL-13 reprogramming by the integrated stress response.
Immunometabolic Dysregulation in Obesity: Integrating Macrophage Polarization, Metabolic Reprogramming, and Gut Microbiota Crosstalk.
Metabolic inflammation, obesity, and cancer.
Mitochondrial Complex II in the regulation of immunopathology.
Metabolic-epigenetic rewiring of CCR5hi monocytes sustains long-term trained immunity against lethal sepsis.
PKM2: A gatekeeper in macrophage metabolic reprogramming.
Nicotinamide Metabolism Constrains Memory CD8+ T Cell Formation Through a Putative HS1BP3-SIRT1-FOXO3-BCL6 Axis.
Time-resolved multi-omics reveals macrophage-centered immunometabolic remodeling in cutaneous dematiaceous fungal infection.
Unconventional role of hydroxymethylglutaryl-CoA synthase 1 in driving pathogenic TH17 cell immunity and autoimmune diseases.
Metabolic activation using fructose-1,6-bisphosphate microparticles of non-virally LNP-generated CAR-macrophages induces anti-tumor immune responses.
Long-chain fatty acid metabolism reprograms antitumor immunity: from molecular mechanisms to clinical translation.
PD-L1 restrains T-cell immunity in Nile tilapia by suppressing activation-induced fatty acid synthesis.
ALK regulates macrophage polarization via the USP7/SOX9/MFAP2-mediated glycolytic pathway to promote neuroblastoma progression.
Hcp1 mediates multinucleated giant cell formation through redirecting arginine metabolism during Burkholderia pseudomallei infection.
Intestinal cGAS-STING-IFN signalling promotes obesity by downregulating microbiota-derived IAA in male mice.
Decoding Immunometabolic Dynamics of Adipose Tissue in Obesity: Evolving Evidence and Way Forward.
Tumor-driven arginine depletion induces T-cell metabolism reprogramming to suppress atherosclerosis in colorectal cancer.
Lactate controls glomerular endothelial barrier integrity in lupus nephritis.
The K247 ubiquitination site of the Newcastle disease virus M protein enhances viral budding to facilitate rapid exploitation of host cell sphingolipid metabolites.
PFAS penetrate the bone marrow microenvironment and alter immunometabolic homeostasis.
Time-restricted eating, immunomodulation and ketone metabolism in humans.
MOTS-c is a mitochondrial-encoded interferon-linked host defense peptide.

Scand J Immunol. 2026 Aug;104(2): e70141

Evolution and Mechanistic Insights of Immunometabolism in Metabolic Diseases and Infections.

Wenbin Tan.

  Immunometabolism, an emerging field exploring metabolic reprogramming and functional regulation in immune cells, offers a lens for understanding complex diseases. This review delineates core concepts, key signalling nodes-emphasising the mechanistic target of rapamycin (mTOR) as an integrator of metabolic and immune signals-research and intervention strategies across metabolic and infectious diseases. Immune cells display metabolic plasticity: At rest, they depend mainly on mitochondrial oxidative phosphorylation, but swiftly shift to aerobic glycolysis upon activation to fuel effector functions. Pro-inflammatory subsets like Th1 cells and M1 macrophages lean heavily on glycolysis, whereas regulatory T cells favour fatty acid oxidation. Central pathways-glycolysis, the tricarboxylic acid (TCA) cycle, and amino acid metabolism-directly shape immune activation and inflammation via intermediates and regulatory enzymes. For example, succinate and itaconic acid are critical in inflammation control, while fatty acid and cholesterol metabolism dictate immune cell fate. In metabolic disorders such as obesity, diabetes, fatty liver disease, and atherosclerosis, immune metabolic reprogramming is the main driver of chronic low-grade inflammation and tissue injury. During infection, a metabolic tug-of-war ensues: Pathogens hijack host metabolism for survival, and the host counters by reprogramming its own metabolism. The idea of "trained immunity" highlights how metabolism-epigenetics crosstalk endows innate immunity with memory-like capacity. These insights inform therapeutic avenues-modulating metabolic pathways, nutritional interventions, and microbiome targeting-with wide potential. Challenges remain, including the complexity of in vivo networks and the need for precise interventions. Yet advances in single-cell multi-omics and metabolic flux analysis will deepen mechanistic understanding and enable breakthroughs in precision strategies.

Keywords:  immunometabolism; infection; metabolic diseases; metabolic reprogramming; trained immunity

DOI:  https://doi.org/10.1111/sji.70141
bioRxiv. 2026 Aug 04. pii: 2026.08.03.742570. [Epub ahead of print]

SAMHD1 enhances HIV-1-induced glycolysis in monocytic cells through hexokinase 2 upregulation.

Hua Yang, Pak-Hin Hinson Cheung, Li Wu.

SAMHD1 is a mitochondria-associated cellular protein that restricts HIV-1 replication by depleting intracellular dNTP pools in non-dividing immune cells, such as macrophages, dendritic cells, and resting CD4 + T cells; however, its role in host metabolism remains unclear. Building on our previous finding that SAMHD1 promotes mitochondrial membrane damage in HIV-1-infected monocytic cells, here we identify a new function for SAMHD1 in enhancing HIV-1-induced glycolysis through upregulation of hexokinase 2 (HK2). In monocytic THP-1 cells, but not differentiated macrophage-like cells, SAMHD1 amplifies HIV-1-triggered glucose uptake and basal glycolysis. Mechanistically, SAMHD1 increases HK2 expression and promotes its cytosolic accumulation, leading to elevated reactive oxygen species (ROS) production. This SAMHD1-dependent metabolic rewiring links antiviral restriction to glycolytic control and cellular stress responses. Our findings reveal a cell state-specific role for SAMHD1 in regulating glycolysis during HIV-1 infection, identify HK2 as a key effector, and uncover an unanticipated layer of host-virus interaction in monocytic cells.
IMPORTANCE: SAMHD1 is best known as a restriction factor that inhibits HIV-1 replication mainly through its dNTPase activity. However, emerging evidence suggests that SAMHD1 also regulates mitochondrial homeostasis and cellular metabolism. We previously demonstrated that SAMHD1 promotes HIV-1-induced apoptosis in monocytic cells through a mitochondrial pathway, implicating SAMHD1 in the control of mitochondrial function during infection. Because mitochondria are central regulators of cellular energy metabolism, we investigated whether SAMHD1 influences glycolytic reprogramming in HIV-1-infected monocytic cells. Our results show that SAMHD1 enhances glucose uptake, glycolysis, HK2 expression, and ROS production during HIV-1 infection. These findings reveal a previously unrecognized role for SAMHD1 in coordinating metabolic and oxidative stress responses to HIV-1 infection and provide new mechanistic insight into the interplay between antiviral factors, cellular metabolism, and HIV-1 pathogenesis. Understanding how SAMHD1 regulates glucose metabolism may uncover novel links between innate immune defenses and metabolic disease.

DOI: https://doi.org/10.64898/2026.08.03.742570
bioRxiv. 2026 Jul 29. pii: 2026.07.28.740519. [Epub ahead of print]

Distinct spatiotemporal immunometabolic remodeling following acute traumatic brain injury.

Zohreh Erfani, Erin H Seeley, Erik J Plautz, Brenda L Bartnik-Olson, Jae Mo Park.

Traumatic brain injury induces profound metabolic reprogramming across neurons, astrocytes, and microglia, yet the spatiotemporal organization of these metabolic responses remains poorly understood. Because pyruvate is uniquely positioned in cerebral metabolism by connecting glycolysis, lactate metabolism, and the tricarboxylic acid cycle, we combined matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging with in vivo administration of isotopically labeled pyruvate and immunohistochemistry to characterize cell-type-wise metabolic remodeling in a controlled cortical impact rat model during the acute and subacute phases of injury. TBI induced distinct spatiotemporal immunometabolic remodeling across neuroglial compartments. Microglia- and macrophage-enriched regions exhibited selective accumulation of citrate, succinate, and itaconate, consistent with inflammatory metabolic rewiring. In contrast, astrocyte enriched regions showed increased glutamine and malate abundance, indicative of altered neuron-astrocyte metabolic coupling such as remodeling of the glutamate-glutamine cycle and enhanced anaplerotic metabolism. These metabolic signatures evolved with distinct regional and temporal distributions, identifying compartmentalized metabolic responses. Notably, labeled isotopologues of selected metabolites, including glutamate and citrate derived from administered pyruvate, changed before the corresponding metabolite pools. Together, these findings describe the spatiotemporal landscape of immunometabolic remodeling following acute TBI, uncover metabolically distinct microglial/macrophage and astrocytic responses during secondary brain injury, and identify candidate metabolic pathways for therapeutic intervention and metabolic imaging.

DOI: https://doi.org/10.64898/2026.07.28.740519
Nat Cancer. 2026 Aug 18.

A lactate-α-ketoglutarate metabolic circuit in tumor-infiltrating regulatory T cells accelerates tumor progression by inducing NK cell senescence.

Tiezhu Shi, Yufeng Ding, Ying Chen, Xiangyin Tan, Fangfang Qu, Dongwei Xu, Xinyu Liu, Yixue Li, Yan-Fang Liu, Xiaolin Zhang, Guanzhen Yu, Jialiang Shao, Xiongjun Wang.

Regulatory T (Treg) cells prevent autoimmune diseases but limit antitumor immunity. Tumor‑infiltrating Treg (Ti‑Treg) cells exhibit metabolic traits as potential antitumor targets. Here, we find that Ti-Treg cells upregulate glutamate dehydrogenase 1 (GDH1), increasing α-ketoglutarate (α-KG) levels. Elevated GDH1 in Ti-Treg cells accelerates tumor progression. Mechanistically, in a lactate rich microenvironment, GDH1 lactylation boosts α-KG production to fuel ALKBH5-mediated Wnt2 expression in Ti-Treg cells. Enhanced WNT2 promotes natural killer (NK) cell senescence. GDH1 inhibition or SLC16A1 deletion in Ti-Treg cells reduces NK senescence and improves adoptive NK transfer therapy. We reveal a lactate-α‑KG metabolic circuit driving NK senescence, offering therapeutic targets to boost antitumor immunity.

DOI: https://doi.org/10.1038/s43018-026-01210-6
Sci Adv. 2026 Aug 21. 12(34): eaed6318

Mitochondrial profiling across macrophage states reveals inhibition of IL-4/IL-13 reprogramming by the integrated stress response.

Joan Blanco-Fernandez, Miriam Lisci, Mads M Foged, Chloé Chapuis, Tim Pflästerer, Tatjana Kleele, Alexis A Jourdain.

Mitochondria drive cellular reprogramming by integrating metabolism and signaling. In macrophages, mitochondria are central to immunometabolic responses to external cues, but the extent to which they are remodeled and participate in macrophage reprogramming remains unclear. Here, we integrate transcriptomics with whole-cell and purified mitochondrial proteomics to profile lipopolysaccharide (LPS)/interferon-γ (IFN-γ)- and interleukin-4 (IL-4)/IL-13-stimulated macrophages. We reveal a notable disconnect between mitochondrial transcript and protein levels following either stimulus and a signal transducer and activator of transcription 6 (STAT6)-dependent increase in mitochondrial DNA (mtDNA) expression and intramitochondrial translation in IL-4/IL-13 macrophages. We demonstrate that pharmacological inhibition of mitochondrial translation or individual respiratory chain complexes variably impairs reprogramming, whereas ATP synthase inhibition uniquely triggers a heme-regulated inhibitor (HRI)-dependent integrated stress response (ISR) through mitochondrial hyperpolarization, thereby preventing IL-4/IL-13 reprogramming. Mechanistically, we show that restoring mitochondrial membrane potential or inhibiting the ISR rescues IL-4/IL-13-mediated reprogramming. Together, we identify mtDNA expression, intramitochondrial translation, and mitochondrial membrane potential as critical, drug-sensitive determinants of the IL-4/IL-13 response.

DOI: https://doi.org/10.1126/sciadv.aed6318
Immun Inflamm Dis. 2026 Aug;14(8): e70470

Immunometabolic Dysregulation in Obesity: Integrating Macrophage Polarization, Metabolic Reprogramming, and Gut Microbiota Crosstalk.

Yuanyuan Li, Jingwei Mao, Yiwen Deng, Xiaobo Ge, Limin Nie, Qun Wang, Ruiqing Wang, Jiarun Zhang, Tianli Lyu, Luopeng Zhao, Lu Liu, Bin Li.

   BACKGROUND: Obesity is characterized by chronic low-grade systemic inflammation, in which adipose tissue macrophages (ATMs) play a pivotal role in driving immune and metabolic dysfunction.
OBJECTIVE: This review summarizes current evidence on the roles of ATMs in obese adipose tissue and examines how macrophage polarization and metabolic reprogramming are linked to fatty acid metabolism, insulin resistance (IR), and gut microbiota dysbiosis.
RECENT FINDINGS: Previous studies have often addressed macrophage dysfunction, fatty acid metabolism, IR, and gut microbiota alterations as separate processes. In contrast, this review integrates these obesity-related events within a unified immunometabolic framework centered on ATMs. Obesity induces marked phenotypic shifts and metabolic reprogramming in ATMs, thereby promoting chronic inflammation and IR. Disturbed fatty acid metabolism and gut microbiota dysbiosis further impair metabolic homeostasis and intestinal barrier integrity, reinforcing a vicious cycle of macrophage-driven immunometabolic dysfunction.
CONCLUSIONS: This review highlights the central role of ATM-mediated immune-metabolic crosstalk in obesity and emphasizes the therapeutic potential of targeting macrophage dysfunction and gut microbiota alterations to attenuate obesity-related metabolic complications.

Keywords:  gut microbiota; inflammation; macrophage; metabolism; obesity

DOI:  https://doi.org/10.1002/iid3.70470
Immunity. 2026 Aug 20. pii: S1074-7613(26)00319-5. [Epub ahead of print]

Metabolic inflammation, obesity, and cancer.

Fawaz Alzaid, Camille Blériot, Gerasimos Anagnostopoulos, Svetoslav Chakarov, Nicolas Venteclef, Florent Ginhoux.

  Obesity is a global health concern, driving metabolic dysfunction and systemic inflammation. Here, we review the current understanding of the mechanisms underlying the impact of obesity in cancer susceptibility, progression, and response to therapy. We first discuss how resident and recruited macrophages adapt to metabolic stress within adipose tissue and the liver, which are metabolic hub tissues. We consider how obesity-driven myeloid reprogramming extends to other myeloid lineages and influences systemic immune function. Within this framework, where myeloid cells play conserved roles across tissues, we discuss cancer and how obesity-imprinted programs modify antitumor immunity irrespective of tumor site. We propose that local metabolic adaptation results in systemic immune consequences that impact tumor development and progression. Viewing cancer through the lens of obesity-related immunometabolic dysfunction may shed light on tissue- and cancer-specific responses and open avenues to improved therapies and management.

Keywords:  cancer; dendritic cells; macrophages; monocytes; myeloid cells; neutrophils; obesity

DOI:  https://doi.org/10.1016/j.immuni.2026.07.020
Trends Immunol. 2026 Aug 18. pii: S1471-4906(26)00192-4. [Epub ahead of print]

Mitochondrial Complex II in the regulation of immunopathology.

Akira Yamamoto, Yuichi Sumii, Pavan Reddy.

  Mitochondrial complex II, succinate dehydrogenase (SDH), links the tricarboxylic acid cycle to the electron transport chain by oxidizing succinate to fumarate and reducing ubiquinone. This unusual position gives Complex II control over bioenergetics, redox state, succinate signaling, and chromatin regulation. In immune cells, Complex II regulates macrophage responses via the succinate-hypoxia-inducible factor-1α-IL-1β axis, T-cell proliferation, lineage commitment, and cytotoxicity. In target tissues of an aberrant immune attack, such as the intestinal epithelium and stem-cell compartments, SDHA loss lowers tissue tolerance, promotes inflammatory memory through succinate-driven epigenetic reprogramming, and amplifies immune-mediated injury. In tumors, SDH loss increases antigen presentation and their susceptibility to T-cell killing. Complex II, therefore, regulates immunopathology through its actions within both attacking immune cells and injured target tissues.

Keywords:  immunometabolism; mitochondrial Complex II; succinate dehydrogenase

DOI:  https://doi.org/10.1016/j.it.2026.07.013
Sci Adv. 2026 Aug 21. 12(34): eaee1634

Metabolic-epigenetic rewiring of CCR5hi monocytes sustains long-term trained immunity against lethal sepsis.

Lingqi Xu, Wenyan Hao, Yingyi Yang, Yu Wang, Yaoshuang Li, Yuan Gong, Yifang Ding, Jie Huang, Zhenjiang Bai, Qiang Shan, Rui Kang, Jiang Huai Wang, Haichao Wang, Timothy R Billiar, Jian Wang, Daolin Tang, Huiting Zhou.

Trained immunity enhances innate host defense by endowing monocytes with memory-like properties, yet the underlying integrated metabolic and epigenetic mechanisms remain elusive. Here, we demonstrate that coimmunization with Bacille Calmette-Guérin (BCG) and bacterial lipoprotein (BLP) induces a durable form of trained immunity that provides robust, long-term protection against polymicrobial sepsis from early life into adulthood. Single-cell RNA sequencing revealed that this effect is mediated by an expansion of CCR5hi memory-like monocytes with enhanced antimicrobial capacity. Mechanistically, BCG + BLP vaccination activated the AKT-mTOR-HIF-1α axis, driving glycolytic reprogramming and lactate accumulation. Elevated lactate enhanced KAT2B-dependent histone H3K18 lactylation, an epigenetic mark directly facilitating the transcription of phagocytic and inflammatory genes. In addition, BCG + BLP stimulation of human cord blood mononuclear cells induced CCR5hi monocytes that recapitulated trained immunity features. These findings identify a lactate-KAT2B-H3K18la epigenetic axis that orchestrates the long-term reprogramming of CCR5hi monocytes, highlighting CCR5hi monocytes as a promising therapeutic target for modulating innate immunity against lethal sepsis.

DOI: https://doi.org/10.1126/sciadv.aee1634
J Pharm Anal. 2026 Aug;16(8): 101564

PKM2: A gatekeeper in macrophage metabolic reprogramming.

Ke Li, Mingyu Wu, Qiuyu Zhang, Jiabin Wu, Xianyi Ding, Weihua Xiao.

  Metabolic reprogramming serves as a core adaptive mechanism for cells to respond to microenvironmental changes and plays a decisive role in macrophage functional polarization. Pyruvate kinase M2 (PKM2), recognized for its dynamic allosteric regulation, acts as a critical molecular hub linking metabolic reprogramming with immune responses. Despite numerous studies affirming the pivotal role of PKM2 in tumor metabolism, its complex regulatory mechanisms within the immune metabolic network remain inadequately defined, significantly hindering the advancement of targeted therapeutic strategies for metabolic reprogramming. This review meticulously analyzes and highlights the significance of PKM2-mediated metabolic reprogramming in macrophages across several organ disorders. We subsequently examined various PKM2 inhibitors and activators, along with natural compounds that modulate PKM2, as research evidence for therapeutic approaches to diseases, particularly with the metabolic reprogramming of macrophages. This study comprehensively examines the theoretical foundation, research evidence, and intervention strategies regarding PKM2 as a crucial regulatory element of macrophages, offering novel perspectives on therapeutic approaches for macrophage metabolic reprogramming.

Keywords:  Macrophage; Metabolic reprogramming; Pyruvate kinase M2; Therapeutic strategies

DOI:  https://doi.org/10.1016/j.jpha.2026.101564
Adv Sci (Weinh). 2026 Aug 21. e77284

Nicotinamide Metabolism Constrains Memory CD8+ T Cell Formation Through a Putative HS1BP3-SIRT1-FOXO3-BCL6 Axis.

Siyang Wang, Xiaoqian Fan, Yifan Huang, Chang Yao, Jixing Fan, Yu Ping, Xuan Zhao, Congcong Li, Chunyi Shen, Jiqi Shan, Jinyan Liu, Shengdian Wang, Zhen Zhang, Yi Zhang.

  Memory T cells exhibit long-term persistence, a defining feature that underpins durable clinical responses to adoptive immunotherapies. The mechanisms that integrate metabolic cues with transcriptional control of memory fate remain undetermined. Here, we identify HS1-binding protein 3 (HS1BP3) is preferentially expressed in memory CD8+ T cells. HS1BP3 deficiency reduced memory-associated gene expression in CD8+ OT-1 T cells following Listeria monocytogenes-ovalbumin infection and impaired antitumor responses. Loss of HS1BP3 induces metabolic reprogramming characterized by reduced oxidative phosphorylation (OXPHOS) and altered nicotinamide metabolism, accompanied by increased NAD+ and nicotinamide metabolite 1-methylnicotinamide (MNAM) abundance. HS1BP3 interacted with Sirtuin 1 (SIRT1), and its deficiency is associated with increased SIRT1 activity, enhanced Forkhead box O3 (FOXO3) signaling, and reduced expression of memory-associated transcription factor B cell lymphoma 6 (BCL6). Moreover, accumulation of MNAM impairs the antitumor activity of CD8+ T cells. Importantly, elevated levels of HS1BP3 drive chimeric antigen receptor (CAR) -T cells towards a memory phenotype and improve tumor control. Collectively, our findings identify HS1BP3 as a regulator of CD8+ T cell memory and indicate that its effects are associated with alterations in nicotinamide metabolism and the SIRT1-FOXO3-BCL6 signaling axis. These observations support the therapeutic potential of HS1BP3-engineered CAR-T cells across solid tumors.

Keywords:  CD8+ T cell; antitumor response; memory; nicotinamide metabolism

DOI:  https://doi.org/10.1002/advs.77284
Front Immunol. 2026 ;17 1893423

Time-resolved multi-omics reveals macrophage-centered immunometabolic remodeling in cutaneous dematiaceous fungal infection.

Yongqiang Fu, Mengying Liu, Qi Dong, Xinyu Guo, Jiejie Lu, Weiwei Wu, Hiroki Takahashi, Ruijun Zhang.

   Background: Dematiaceous fungi cause chronic, invasive cutaneous infections that are difficult to eradicate and frequently relapse despite antifungal therapy. Although host immunity is critical for controlling these infections, the temporal organization of immune responses and the underlying immunometabolic programs remain poorly defined. In particular, how macrophage dynamics and chemokine signaling shape antifungal immunity over time is largely unknown.
Methods: Using Phialophora verrucosa as a representative dematiaceous fungus, we established a murine subcutaneous infection model and performed time-resolved transcriptomic and proteomic analyses across the course of infection. Immune cell composition, pathway dynamics, and metabolic signatures were systematically characterized. To functionally validate key regulatory axes identified by multi-omics analyses, bone marrow-derived macrophages and dendritic cells from wild-type and Ccr2 knockout mice were subjected to in vitro fungus-cell coculture assays.
Results: Time-resolved multi-omics analysis revealed that days 7-14 post-infection constituted a critical transition phase of the host immune response, coinciding with lesion regression and pathogen clearance. This stage featured marked activation of pathways governing antigen presentation, phagosome formation and inflammatory signaling. Macrophages underwent dynamic changes in both abundance and phenotype during this period, accompanied by the upregulation of glycolysis- and lactate metabolism-related pathways. Co-expression and interaction network analysis further identified Ccr2 as a core hub within the chemokine signaling network. in vitro functional assays demonstrated that while Ccr2 deficiency did not compromise the phagocytic or fungicidal activity of macrophages, it significantly diminished their chemotactic capacity toward P. verrucosa conidia. Under infection stimulation, loss of Ccr2 also promoted M1-type polarization of macrophages, along with enhanced maturation of dendritic cells.
Conclusions: This study elucidates the dynamic remodeling of immunometabolism centered on macrophages during P. verrucosa infection, and demonstrates that the CCL2/CCR2 biological axis contributes to host antifungal immunity mainly by modulating immune cell recruitment and the balance of inflammatory phenotypes. These findings provide a novel theoretical basis for understanding the immunoregulatory mechanisms of dematiaceous fungal infections and developing potential immunological intervention strategies.

Keywords:  CCR2; Phialophora verrucosa; cutaneous infection; dematiaceous fungi; immunometabolism; macrophages; time-resolved multi-omics

DOI:  https://doi.org/10.3389/fimmu.2026.1893423
Sci Adv. 2026 Aug 21. 12(34): eaee4337

Unconventional role of hydroxymethylglutaryl-CoA synthase 1 in driving pathogenic TH17 cell immunity and autoimmune diseases.

Jie Sun, Yali Lei, Huanhuan Yang, Shu Li, Bing Wu.

T helper 17 (TH17) cells are heterogeneous and able to adopt pathogenic and non-pathogenic phenotypes. Identifying factors controlling pathogenic TH17 cells is of importance for their vital role in inflammation and immune-pathology. Here, we demonstrated that HMGCS1, a cholesterol biosynthesis precursor enzyme, was highly induced by inflammatory cytokines and preferentially expressed by pathogenic TH17 cells in vitro and in vivo. HMGCS1 specifically dictated pathogenic TH17 cell differentiation and augmented autoimmune diseases, yet it has no discernible effect on nonpathogenic TH17 cells. Unexpectedly, this role is independent of its canonical function in cholesterol metabolism but requires its catalytic Cys129 residue. Notably, HMGCS1 governs pTH17 cell generation and pathogenicity by leveraging an IRE1α-XBP1s-dependent ER stress response, which in turn transcriptionally activates the lineage-defining factor RORγt (encoded by Rorc). Mechanistically, HMGCS1 is located to the ER membrane, where it bound and stabilized IRE1α protein. This stabilization is achieved by preventing IRE1α's interaction with the E3 ubiquitin ligase MARCH5, thereby inhibiting its K48-linked ubiquitination and subsequent degradation. Moreover, interfering with HMGCS1 or the ER stress response in T cells impedes pTH17 immunity and mitigates autoimmune disease in vivo. Therefore, our work unveils a noncanonical axis in which HMGCS1 sustains ER stress to license pTH17 differentiation during autoimmune responses.

DOI: https://doi.org/10.1126/sciadv.aee4337
J Mater Chem B. 2026 Aug 17.

Metabolic activation using fructose-1,6-bisphosphate microparticles of non-virally LNP-generated CAR-macrophages induces anti-tumor immune responses.

Abhirami P Suresh, Huikang Qian, Vinayak Uppin, Abhirami Thumsi, Da Sun, Madhan Mohan Chandra Sekhar Jaggarapu, Joslyn Mangal, Sahil Inamdar, Zheng-Rong Lu, Reshmi Parameswaran, Abhinav P Acharya.

While chimeric antigen receptor (CAR)-T cell therapy has demonstrated remarkable clinical efficacy in hematological malignancies, its impact on solid tumors remains limited, largely due to insufficient T cell infiltration into the tumor microenvironment (TME). In contrast, macrophages are inherently recruited to the TME, offering a promising platform for cell-based immunotherapy. However, the nutrient-deprived conditions within the TME drive macrophages toward an immunosuppressive, tumor-promoting phenotype, thereby constraining their therapeutic potential. Here, we report a metabolic accelerating strategy designed to potentiate the anti-tumor activity of CAR-engineered macrophages (CAR-macs) by increasing their glycolytic capacity. We demonstrate that pre-treatment of CAR-macs with microparticles generated from fructose 1,6-bisphosphate (F16BP) can augment glycolytic flux and promote pro-inflammatory polarization. In a murine lymphoma solid tumor model, this approach significantly enhances anti-tumor immune cell responses and demonstrates that the CAR-macs are able to home to the tumor site. Our findings establish a novel paradigm in CAR macrophage-based immunotherapy, demonstrating that metabolic reprogramming can overcome the immunosuppressive TME and substantially improve therapeutic efficacy against solid tumors.

DOI: https://doi.org/10.1039/d6tb01143h
Biochem Pharmacol. 2026 Aug 20. pii: S0006-2952(26)00716-1. [Epub ahead of print] 118377

Long-chain fatty acid metabolism reprograms antitumor immunity: from molecular mechanisms to clinical translation.

Guo Guo, Huang Xin, Weng Xiufang.

  This review summarizes how LCFA metabolic enzymes and transporters orchestrate antitumor immunity, underscoring their cell-type-specific dualities and druggability. AlphaFold3-predicted structures of CPT1A, ACSL4, ACSL5, FABP4, FABP5, and CD36 reveal deep hydrophobic pockets (Fpocket scores 0.67-0.81), and molecular docking maps inhibitor interactions: etomoxir (CPT1A His473 covalent), PRGL493 (ACSL4 AMP pocket), triacsin C (ACSL5 substrate tunnel), SBFI-26 (FABP5 β-barrel), and sulfo-N-succinimidyl oleate (CD36 SMAC pocket). Certain dietary LCFAs potently enhance antitumor responses: elaidic acid promotes MHC-I antigen presentation via the ACSL5-SIRT6-NLRC5 axis, sensitizing tumors to CD8+ T-cell-mediated killing and immune checkpoint blockade; docosahexaenoic acid (DHA) incorporates into phospholipids via ACSL4/6 to drive immunogenic ferroptosis, amplified by CD8+ T-cell-derived IFN-γ. In contrast, chronic LCFA accumulation fosters an immunosuppressive landscape: CPT1A-dependent FAO sustains Tregs, yet its succinyltransferase activity promotes PD-L1 degradation; myeloid FABP5 drives immunosuppressive macrophage differentiation; and CD36-mediated uptake of lipids or oxidized lipoproteins induces CD8+ T-cell dysfunction via the p38-CEBPB-TfR1 cascade and iron-dependent lipid peroxidation. Moreover, tumor-intrinsic ACSL4 can alternatively promote neoplastic proliferation and therapeutic resistance, revealing an oncogenic facet. Accordingly, we assess translational strategies that target these metabolic nodes in a context-aware manner: context-dependent CPT1A inhibition or non-enzymatic activation; selective blockade of CD36 or FABP5; inhibition of oncogenic ACSL4; and complementary approaches harnessing ACSL4/5-mediated antitumor pathways (e.g., ferroptosis induction and antigen presentation enhancement) through tailored dietary interventions and combination therapies. This integrated structural, biochemical, and pharmacological framework highlights the necessity of uncoupling the opposing immunomodulatory roles of LCFAs using cell-type-resolved and context-aware strategies in cancer therapy.

Keywords:  Antitumor immunity; Fatty acid oxidation; Ferroptosis; Immune checkpoint blockade; Long-chain fatty acids; Metabolic reprogramming

DOI:  https://doi.org/10.1016/j.bcp.2026.118377
J Immunol. 2026 Aug 04. pii: vkag236. [Epub ahead of print]215(8):

PD-L1 restrains T-cell immunity in Nile tilapia by suppressing activation-induced fatty acid synthesis.

Jiansong Zhang, Kunming Li, Yuqing Yang, Shiqi Tang, Kang Li, Jialong Yang, Xiumei Wei.

  The programmed death ligand 1/programmed cell death 1 (PD-L1/PD-1) serves as a critical immune checkpoint in T cell-mediated immune responses, playing a central role in maintaining peripheral immune tolerance and homeostasis. Although early vertebrates lack a PD-1 homolog and they retain PD-L1, the functional significance and regulatory mechanisms of PD-L1 in T-cell immunity in these species remain poorly understood. In this study, using Nile tilapia (Oreochromis niloticus) as a teleost model, we systematically investigated the immunosuppressive role of PD-L1 in T-cell immunity. PD-L1 was widely expressed in various lymphoid tissues, and both its mRNA and protein levels were significantly upregulated following T-cell activation induced by mAbs against CD3/CD28 and Edwardsiella piscicida infection. Functional analyses demonstrated that exogenous PD-L1 treatment markedly suppressed T-cell activation and promoted activation-induced apoptosis. Moreover, PD-L1 treatment significantly impaired T-cell proliferation, effector cytokine production, and cytotoxic activity, ultimately compromising antibacterial immune defense. Mechanistically, activated tilapia T cells exhibited enhanced de novo fatty acid synthesis, whereas PD-L1 disrupted this metabolic reprogramming by inhibiting key enzymatic activities and reducing acetyl-CoA accumulation, ultimately leading to impaired T-cell function. Notably, restoration of fatty acid synthesis effectively reversed the PD-L1-induced immunosuppressive effects on tilapia T cells. In summary, this study reveals a previously unrecognized mechanism by which PD-L1 suppresses T-cell immunity in an early vertebrate through modulation of lipid metabolism. These findings highlight the essential role of metabolism regulation in immune checkpoint signaling and provide new evolutionary insights into the maintenance of T-cell homeostasis.

Keywords:  PD-L1; T cells; fatty acid synthesis; tilapia

DOI:  https://doi.org/10.1093/jimmun/vkag236
Cell Signal. 2026 Aug 15. pii: S0898-6568(26)00482-1. [Epub ahead of print]148 112824

ALK regulates macrophage polarization via the USP7/SOX9/MFAP2-mediated glycolytic pathway to promote neuroblastoma progression.

Caimin Lai, Kunting Xu, Renfu Li, Jianxing Chen, Ziyi Zheng, Min Zhong, Yang Wang, Zhiyong Shen, Feng Chen.

  Neuroblastoma (NB) is a common pediatric malignancy in which activating mutations of anaplastic lymphoma kinase (ALK) drive tumor progression, yet the underlying mechanisms remain incompletely understood. Here, we demonstrate that ALK signaling promotes glycolysis and M2 macrophage polarization through the USP7-SOX9-MFAP2 axis. Using qRT-PCR, western blot, and co-culture systems, we found that ALK inhibition with lorlatinib reduces lactate production, downregulates M2 markers, and upregulates M1 markers in NB cells and NB mouse models. Mechanistically, Co-IP and ubiquitination assays revealed that ALK recruits and activates the deubiquitinase USP7, which deubiquitinates and stabilizes SOX9. Dual-luciferase reporter and ChIP-qPCR analyses further demonstrated that SOX9 directly binds to the MFAP2 promoter to activate its transcription. Functional assays showed that elevated MFAP2 enhances glycolysis, leading to increased lactate and immunosuppressive factor secretion, which in turn polarizes tumor-associated macrophages toward the pro-tumor M2 phenotype. Importantly, in vivo experiments confirmed that MFAP2 overexpression partially reverses the anti-tumor effects of lorlatinib. These findings identify the ALK/USP7/SOX9/MFAP2 cascade as a critical regulator of metabolic reprogramming and immune evasion in NB, and suggest that targeting this axis may represent a promising therapeutic strategy for high-risk NB.

Keywords:  ALK; Glycolysis; MFAP2; Macrophage polarization; Neuroblastoma

DOI:  https://doi.org/10.1016/j.cellsig.2026.112824
Cell Rep. 2026 Aug 19. pii: S2211-1247(26)00946-0. [Epub ahead of print]45(9): 117868

Hcp1 mediates multinucleated giant cell formation through redirecting arginine metabolism during Burkholderia pseudomallei infection.

Pan Wu, Beibei Fu, Dongqi Nan, Yuan Wen, Hengyu Wang, Ziyuan Zhang, Chenglong Rao, Xiaoxue Lu, Mengru Wang, Yong Sheng, Jingmin Yan, Guangqiang Zhao, Senquan Zheng, Changhao Yao, Kewei Yu, Ling Deng, Xiaoyuan Lin, Xuhu Mao, Zhiqiang Hu, Qian Li.

  Melioidosis is a life-threatening infectious disease caused by Burkholderia pseudomallei with limited therapeutic options. Multinucleated giant cell (MNGC) formation is known to facilitate B. pseudomallei dissemination and melioidosis progression, yet the underlying mechanism remains unclear. Here, we show that the type VI secretion system effector Hcp1 promotes MNGC formation by targeting host arginase-1 (ARG1). Hcp1 modifies ARG1 at residues 78 and 86, enhances its enzymatic activity, and redirects arginine metabolism toward polyamine biosynthesis. Polyamine accumulation upregulates transcription of endothelial selectin (E-selectin), a cell adhesion molecule required for intercellular fusion. Elevated E-selectin in turn promotes MNGC assembly and accelerates B. pseudomallei dissemination. Pharmacological ARG1 inhibition or siRNA-mediated Sele knockdown confers significant protection against B. pseudomallei infection in murine models. These findings identify a host-directed mechanism by which Hcp1 drives bacterial dissemination and establish the Hcp1-ARG1-E-selectin axis as a potential host-directed therapeutic target.

Keywords:  Burkholderia pseudomallei; CP: microbiology; arginase-1; endothelial selectin; hemolysin coregulated protein 1; multinucleated giant cell

DOI:  https://doi.org/10.1016/j.celrep.2026.117868
Nat Metab. 2026 Aug;8(8): 1713-1729

Intestinal cGAS-STING-IFN signalling promotes obesity by downregulating microbiota-derived IAA in male mice.

Jiangming Deng, Wen Meng, Yuanqin Yang, Ting Xiao, Zhangliu Jin, Jing Wang, Qing-Xin Li, Lingxiang Xie, Jingyi Hu, Rong Song, Yibo Hu, Yi Chu, Qing Li, Ping Jin, Zheng Wang, Irene Xy Wu, Feng Liu, Yang Xiao.

The gut constantly interacts with both pathogens and dietary signals, but how it balances immune and metabolic responses remains unclear. Here we show that intestinal cGAS, a key DNA sensor, acts as a regulator linking gut immunity to whole-body metabolism. We show that cGAS signalling is activated in the intestines of humans and male mice with obesity, leading to increased type I interferon production and heightened immune activity in intestinal cells. Strikingly, deleting cGAS specifically in intestinal epithelial cells enhances energy expenditure, protects against diet-induced obesity and improves metabolic health. These effects depend on the gut microbiota, particularly Lactobacillus murinus and its metabolite indole-3-acetic acid (IAA), which promotes adipose thermogenesis. Our findings position intestinal cGAS as a key driver of obesity through gut-to-fat signalling and suggest that targeting the intestinal cGAS-microbiota IAA axis could offer promising strategies to combat obesity and related metabolic diseases.

DOI: https://doi.org/10.1038/s42255-026-01562-4
ACS Pharmacol Transl Sci. 2026 Aug 14. 9(8): 2024-2043

Decoding Immunometabolic Dynamics of Adipose Tissue in Obesity: Evolving Evidence and Way Forward.

Kajal Kumari, Kanika Verma, Richa Yadav, Jaya Dwivedi, Sarvesh Paliwal, Swapnil Sharma.

  Obesity is a prevalent global health condition associated with an increased risk of cardiovascular and metabolic diseases. Despite the transformative impact of GLP-1 receptor agonists and dual or triple incretin agonists in obesity management, a significant subset of patients develops therapeutic resistance, exhibits no weight loss, or experiences weight regain after treatment discontinuation. These limitations underscore critical gaps in understanding the biological mechanisms underlying the heterogeneity in drug responsiveness. Growing evidence indicates that adipose tissue is a dynamic immunometabolic organ in which chronic low-grade inflammation perturbs metabolic homeostasis and modulates the therapeutic responsiveness. This Review integrates emerging mechanistic, translational, and multiomics evidence on obesity-induced remodeling of adipose immune-cell niches. It also delineates the effects of these alterations, including impaired lipolysis, insulin resistance, defective thermogenesis, and resistance to weight loss. Overall, this Review highlights adipose tissue immunometabolism as a central yet often underappreciated contributor to therapeutic responsiveness and a promising target for future obesity therapies.

Keywords:  adipose tissue; immune cells; immunometabolism; metabolism; obesity

DOI:  https://doi.org/10.1021/acsptsci.6c00071
Acta Pharmacol Sin. 2026 Aug 17.

Tumor-driven arginine depletion induces T-cell metabolism reprogramming to suppress atherosclerosis in colorectal cancer.

Wen-Jun Ni, He-Yang Sun, Meng-Lei Chen, Yu-Zhang Shao, Cong-Cong Ma, Zhao-Yun Xu, Xue-Yu Wang, Shan Zhong, Wen-Xiu Li, Ying Zhang, Yue Wang, Jin-Wei Tian, Mei Hu, Yong Ji.

  The coexistence of atherosclerosis and cancer is increasingly common, yet the influence of tumors on atherogenesis remains poorly understood. In this study, we investigated the impact of colorectal cancer (CRC) on atherosclerosis and elucidated the underlying mechanisms. We analyzed clinical data from patients with concurrent atherosclerosis and CRC and established three murine models of atherosclerosis comorbidity: ApoE-/- and Ldlr-/- mice bearing subcutaneous MC38 tumors, and APCmin/+ApoE-/- mice with spontaneous intestinal adenomas. We found that both patients and mice with concurrent tumors exhibited reduced plaque burden and enhanced plaque stability. Integrative multi-omics analysis comprising single-cell RNA sequencing, spatial transcriptomics, metabolomics, and bulk RNA sequencing revealed that tumors systemically deplete arginine, leading to adaptive metabolic reprogramming of intraplaque T cells toward an oxidative phosphorylation (OXPHOS)-dominant state. This metabolic shift was associated with reduced cytotoxic T-cell infiltration, suppressed pro-inflammatory effector programs, and weakened T cell-macrophage interactions, collectively establishing a low-inflammatory plaque microenvironment. Importantly, dietary arginine supplementation restored T-cell activation and reversed the CRC-mediated atheroprotective effects. These findings reveal a critical role of T-cell immunometabolic reprogramming in cancer-atherosclerosis comorbidity, demonstrate the pronounced context-dependent effects of arginine in advanced atherosclerosis, and highlight plaque-targeted immunometabolic interventions as a promising strategy to modulate plaque progression and stability.

Keywords:  T cells; arginine metabolism; atherosclerosis; colorectal cancer; metabolic reprogramming

DOI:  https://doi.org/10.1038/s41401-026-01899-2
JCI Insight. 2026 Aug 18. pii: e205034. [Epub ahead of print]

Lactate controls glomerular endothelial barrier integrity in lupus nephritis.

Jiaxin Lei, Xingyu Zhai, Yixin Wang, Ying Li, Lei Li, Mengdi Liu, Jing Guo, Lingyi Li, Zhezhuyun Chen, Qinghua Cao, Zhichun Liu, Ting Liu, Lin Xu, Zhenke Wen.

  Systemic lupus erythematosus (SLE) is a progressive autoimmune disease that affects multiple organs and tissues, with lupus nephritis (LN) as one of its most severe complications. While LN progression is associated with compromised permeability of human renal glomerular endothelial cells (HRGECs), the underlying mechanisms are not fully defined. Herein, we demonstrate that aberrant glycolysis drives this glomerular endothelial barrier defect by suppressing the transcription of tight junction (TJ) genes. Mechanistically, circulating self-DNA in SLE plasma acts as a ligand that activates the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway in HRGECs, driving aberrant glycolytic adaption. The resulting glycolytic product, lactate, serves as a substrate for protein lactylation, leading to extensive lactylation and subsequent ubiquitination of the enhancer of zeste homolog 2 (EZH2). In consequence, EZH2 deficiency results in reduced H3K27me3 levels, thereby suppressing the transcription of TJ genes. In a self-DNA-induced SLE model, inhibition of cGAS-STING signaling or lactate production effectively restored the integrity of TJs of HRGECs and concurrently alleviated key LN symptoms. Together, lactate programs lactylation and ubiquitination of EZH2 to impair glomerular endothelial barrier in human SLE.

Keywords:  Autoimmunity; Lupus; Nephrology

DOI:  https://doi.org/10.1172/jci.insight.205034
Poult Sci. 2026 Aug 03. pii: S0032-5791(26)01197-1. [Epub ahead of print]105(11): 107564

The K247 ubiquitination site of the Newcastle disease virus M protein enhances viral budding to facilitate rapid exploitation of host cell sphingolipid metabolites.

Jun Dai, Fanxin Liu, Yiyi Feng, Qinqin You, Jiaojiao Wang, Chan Ding, Xusheng Qiu, Shiji Xiao.

  Newcastle disease virus (NDV), a significant avian paramyxovirus, depends on the acquisition of host-derived membranes for viral envelope assembly during budding. However, the relationship between NDV budding efficiency and host metabolic reprogramming remains incompletely understood. Our previous research demonstrated that the highly virulent strain Herts/33 and the non-virulent strain LaSota differ significantly in budding efficiency, which is attributed to the difference in ubiquitination levels at the K247 site of the M protein. In this study, using recombinant viruses generated in our previous study, we investigated the effects of the K247 ubiquitination site on host cell metabolism. Through RNA sequencing and LC-MS/MS, systematically profiled the transcriptional and metabolic alterations induced by these viruses in HeLa cells. We also compared organ pathology in three-week-old SPF chicks infected with Herts/33 versus LaSota. The results showed that NDV infection broadly reprograms host sphingolipid metabolism. Compared with rLaSota-WT, rLaSota-R247K exhibited higher budding efficiency, linked to accelerated ceramide depletion and a stronger innate immune response. Specifically, rLaSota-R247K infection upregulated interferon- and interleukin-related components such as ISG15, CXCL8, TNF-α, CXCL10, NOD2, CD274, OAS, and IFNB1. Furthermore, we confirmed that blocking the ceramide synthesis pathway significantly suppresses NDV-M protein-mediated budding of VLPs and virions. Pathologically, Herts/33 induced more severe tissue damage than LaSota. Together, these findings indicate that the K247 residue of the NDV M protein enhances viral budding and promotes rapid utilization of host sphingolipids. This work provides mechanistic insight into NDV budding and highlights virus-host metabolic interactions that may inform future antiviral strategies.

Keywords:  Budding; Ceramide; Matrix (M) protein; Newcastle disease virus

DOI:  https://doi.org/10.1016/j.psj.2026.107564
Environ Pollut. 2026 Aug 17. pii: S0269-7491(26)01350-3. [Epub ahead of print]408 128980

PFAS penetrate the bone marrow microenvironment and alter immunometabolic homeostasis.

Sijia Gu, Ji Ma, Xiangying Sun, Keyi Li, Mingzhu Wu, Yumeng Shi, Miao Xu, Hongkai Zhu, Hongwen Sun.

  Per- and polyfluoroalkyl substances (PFAS) are persistent environmental contaminants associated with cancer risk, but their relevance to multiple myeloma remains poorly understood. In an unmatched case-control study of 173 participants, we integrated PFAS biomonitoring, immunoglobulin profiling, and untargeted metabolomics to characterize PFAS-associated immune and metabolic alterations. Higher circulating concentrations of perfluorodecanoic acid and perfluoroheptane sulfonate were associated with increased odds of multiple myeloma and lower polyclonal immunoglobulin G (IgG). Metabolomic analyses identified candidate alterations involving glycolysis, pentose phosphate pathway-related metabolism, redox homeostasis, lipid peroxidation, and arachidonic acid-derived mediators. Several PFAS-IgG and PFAS-metabolic associations were also observed among controls, suggesting that these patterns were not solely attributable to diagnosed multiple myeloma. Complementary PFAS mixture experiments showed lower circulating IgG, reduced bone marrow plasma-cell frequency, and increased serum lactate dehydrogenase activity in mice; experiments in human bone marrow-derived mesenchymal stromal cells showed disrupted redox homeostasis and enhanced oxidative stress. Exploratory mediation analysis further prioritized metabolites potentially mediating the associations between PFAS exposure and multiple myeloma. Together, these findings identify the bone marrow immunometabolic environment as a biologically relevant interface for PFAS-associated effects and support further prospective and targeted experimental investigation.

Keywords:  Glycolysis; Immunometabolism; Metabolomics; Multiple myeloma; PFAS

DOI:  https://doi.org/10.1016/j.envpol.2026.128980
Metabolism. 2026 Aug 21. pii: S0026-0495(26)00266-0. [Epub ahead of print] 156753

Time-restricted eating, immunomodulation and ketone metabolism in humans.

Natalie A Macheret, Geethika P Thota, Aaron Hengist, Amber Courville, Kong Y Chen, Robert J Byrtcha, Rachael J Klein, Noemi Malandrino, Patrycja Puchalska, Peter A Crawford, Daisy Duan, Alex Huang, Thomas C Recupero, Brigit S Sullivan, Michael N Sack, Stephanie T Chung.

   BACKGROUND: Time-restricted eating (TRE) is a popular dietary strategy for supporting weight loss and immune metabolic health, but the underlying mechanisms are unclear.
OBJECTIVE: This narrative mini-review explores the mechanistic associations between TRE, immunomodulation, and ketone body metabolism, focusing on the potential role of ketones in mediating anti-inflammatory responses. Our goals were to synthesize the contemporary literature in humans to identify knowledge gaps that may inform future research directions.
KEY FINDINGS: TRE modestly reduced pro-inflammatory markers and increased circulating ketone concentrations, although the magnitude of these effects was variable and often confounded by the metabolic changes associated with weight loss. Studies isolating TRE from caloric restriction remain limited, and no studies directly assessed the relationship between TRE-induced ketogenesis and immune modulation.
CONCLUSIONS AND FUTURE DIRECTIONS: Ketone bodies may play a key role in mediating the anti-inflammatory effects of TRE, offering a low-risk, non-pharmacological strategy to managing healthy weight and chronic inflammatory conditions. Future studies should prioritize controlled, isocaloric TRE interventions to better define the contributions of ketogenesis and immunomodulation to TRE's health benefits.

Keywords:  Immune; Inflammation; Ketone; Ketone bodies; Metabolism; Time restricted eating; Time restricted feeding

DOI:  https://doi.org/10.1016/j.metabol.2026.156753
Elife. 2026 Aug 18. pii: RP87615. [Epub ahead of print]12

MOTS-c is a mitochondrial-encoded interferon-linked host defense peptide.

Michelle C Rice, Maria Imun, Sang Wun Jung, Chan Yoon Park, Jessica S Kim, Rochelle W Lai, Casey R Barr, Jyung Mean Son, Kathleen Tor, Emmeline Kim, Ryan J Lu, Ilana Cohen, Bérénice A Benayoun, Changhan Lee.

  The mitochondrial DNA (mtDNA) can trigger immune responses and directly entrap pathogens, but it is not known to encode active immune factors. The immune system is traditionally thought to be exclusively nuclear-encoded. Here, we report the identification of a host defense peptide (HDP) encoded in the human mitochondrial genome that presumably derives from the primordial proto-mitochondrial bacteria. We demonstrate that MOTS-c (mitochondrial open reading frame from the 12 S rRNA type-c) is a mitochondrial-encoded amphipathic and cationic peptide with direct antibacterial and immunomodulatory functions, consistent with the peptide chemistry and functions of known HDPs. MOTS-c targeted Escherichia coli and methicillin-resistant Staphylococcus aureus (MRSA), in part, by targeting their membranes using its hydrophobic and cationic domains. In a mouse model of acute peritonitis, MOTS-c fully neutralized MRSA infectivity. In human monocytes, interferon gamma (IFNγ), lipopolysaccharides (LPS), and differentiation signals each induced the expression of endogenous MOTS-c. Notably, exogenous MOTS-c, applied during primary mouse monocyte differentiation, reprogrammed the cells into macrophages with distinct transcriptomic signatures related to antigen presentation and IFN signaling. MOTS-c-programmed macrophages exhibited enhanced bacterial clearance and shifted metabolism. Our findings support MOTS-c as a first-in-class mitochondrial-encoded HDP and indicate that our immune system is not only encoded by the nuclear genome but also by the co-evolved mitochondrial genome.

Keywords:  MOTS-c; cell biology; host defense peptide; human; immunology; inflammation; macrophage; microprotein; mitochondria; mitochondrial immunity; mouse

DOI:  https://doi.org/10.7554/eLife.87615