bims-imicid 2025-12-07 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2025–12–07
35 papers selected by
Dylan Gerard Ryan, Trinity College Dublin

Metabolic reprogramming of CAR T cells: a new frontier in cancer immunotherapy.
Mitochondrial immunometabolism in sepsis: orchestrating macrophage polarization and dysfunction.
Decoding the metabolic crosstalk between glycolysis and RNA viral pathogenesis.
Mitochondrial glutathione transporter SLC25A40 regulates macrophage cytokine production.
Metabolic regulation of T cell production of IL-10 and IL-22 protects against intestinal inflammation.
Editorial: Exploring macrophage metabolic adaptations to bacterial infection: pathways and immune responses.
Restriction of IgA secretion in gut plasma cells is driven by a tissue-specific glycolytic program.
Glycolytic diversity drives immune complexity in cancer.
The roles of sugar metabolism mechanisms and metabolites in viral infections.
Cytochrome c oxidase dependent respiration is essential for T cell activation, proliferation and memory formation.
ApoA1-driven cholesterol efflux and macrophage polarization orchestrate T-cell differentiation towards controlling Leishmania donovani pathogenesis.
Co-culture metabolomics: a powerful tool for uncovering host-pathogen phenotypes driving Burkholderia infections.
SYK regulates Schwann cell metabolic reprogramming to promote axonal regeneration in immune-mediated neuropathy.
Metabolic reprogramming is implicated in the differential response of the CAL-1 plasmacytoid dendritic cell line to autophagy inhibitors.
Dietary Polyunsaturated Fatty Acids Regulate Dendritic Cell Function via Nrf2-dependent Control of Ferroptosis.
The glutamine metabolic switch influences the response of neonatal intestinal macrophages to breast milk.
Innate immune and metabolic signals induce mitochondria-dependent membrane lysis via mitoxyperiosis.
UBE2S-mediated deubiquitination of GLUT1 via USP10 regulates glucose metabolic reprogramming and immune microenvironment to promote fibrosis in endometriosis.
ETV1 Drives CD4+ T Cell-Mediated Intestinal Inflammation in Inflammatory Bowel Disease Through Amino Acid Transporter Slc7a5.
Quiescent ILC1 cells confer protection against MCMV infection during undernutrition.
Comprehensive analysis of metabolism-related genes in sepsis reveals metabolic-immune heterogeneity and highlights GYG1 as a potential therapeutic target.
Activation of the pentose phosphate pathway by microcurrent stimulation mediates antioxidant effects in inflammation-stimulated macrophages.
Oxidative pentose phosphate pathway is required for T cell activation and antitumor immunity.
Lactylation at the crossroads of immune metabolism and epigenetic regulation: revealing its role in rheumatic immune diseases.
mTORC1 signaling in group 2 innate lymphoid cells coordinates neuro-immune crosstalk in allergic lung inflammation.
Positive feedback between histone H4K16 lactylation and glycolysis promotes MAFLD progression.
SIRT3 regulates PDHA1 acetylation in HUVECs to modulate inflammation and pyroptosis under clinorotation.
Loss of Nuclear TDP-43 Impairs Lipid Metabolism in Microglia-Like Cells.
USP5 promotes glycolysis of fibroblast-like synoviocytes by stabilizing the METTL14/m6A/GLUT1 axis in rheumatoid arthritis.
Regulatory T cell transdifferentiation as a driver of obesity and diabetes.
Microglial lipid droplets as therapeutic targets in age-related neurodegenerative diseases.
Spatiotemporal profiling of modification-specific proteome secretion uncovers an itaconation-activated tyrosine kinase.
Adipocytes orchestrate obesity-related chronic inflammation through β2-microglobulin.
β-Hydroxybutyrate ameliorates lipopolysaccharide-induced liver injury through β-hydroxybutyrylation of the SOD2 protein in mice.
Reprogramming of cholesterol sensing in epithelial cells supports pancreatic inflammation.

Front Immunol. 2025 ;16 1688995

Metabolic reprogramming of CAR T cells: a new frontier in cancer immunotherapy.

Tjaša Frlic, Mojca Pavlin.

  Chimeric Antigen Receptor (CAR) T cell therapy has revolutionized hematological cancer treatment, but its efficacy in solid tumors remains limited by the immunosuppressive and metabolically hostile tumor microenvironment (TME). CAR T cells' functional compromise, exhaustion, and poor persistence are critically linked to their suboptimal metabolic fitness. This review highlights a paradigm shift: immunometabolism and its intricate interplay with epigenetics profoundly regulate T cell fate and function, establishing their reprogramming as a cornerstone for optimizing CAR T cell efficacy in diverse malignancies. We explore the intricate relationship between T cell differentiation and metabolic states, emphasizing that modulating CAR T cell metabolism ex vivo during manufacturing can drive differentiation towards less exhausted, more persistent memory phenotypes, such as stem cell central memory (Tscm) and central memory (Tcm) cells, which correlate with superior anti-tumor responses. Our analysis demonstrates that metabolic inhibitors offer significant potential to reprogram CAR T cells. Agents targeting glycolysis or the PI3K/Akt/mTOR pathway promote a memory-like phenotype by favoring oxidative phosphorylation (OXPHOS). Further strategies utilizing glutamine antagonists, mitochondrial modulators, or enzyme manipulation (e.g., IDH2, ACAT1) can epigenetically reprogram cells, fostering memory and exhaustion resistance. Similarly, nutrient level optimization during ex vivo expansion directly sculpts CAR T cell metabolic profiles. With approaches like glucose restriction/galactose substitution, or specific amino acid modulation (e.g., L-arginine, asparagine), persistence of CAR T cells in patients can be improved. The judicious selection and engineering of cytokines (e.g., IL-7, IL-15, IL-21) during manufacturing also plays a vital role in fostering desired memory phenotypes. In conclusion, metabolic engineering, leveraging its impact on epigenetic regulation during CAR T cell manufacturing, is crucial for generating potent, persistent, and functionally resilient products. This approach holds immense promise for expanding the curative potential of CAR T cell therapy to a broader range of cancers, particularly challenging solid tumors.

Keywords:  T cell differentiation; adoptive cell immunotherapy; chimeric antigen receptor (CAR); epigenetics; exhaustion; immunometabolism; metabolic modulation; persistence

DOI:  https://doi.org/10.3389/fimmu.2025.1688995
Eur J Med Res. 2025 Dec 02.

Mitochondrial immunometabolism in sepsis: orchestrating macrophage polarization and dysfunction.

Ke Yang, Qiang Zhao, Youhan Sun, Li Lin, Xiao Han.

  Sepsis is a life-threatening condition marked by dysregulated immune responses and organ dysfunction, with macrophages playing central roles in both hyperinflammation and immunosuppression. Recent advances highlight mitochondrial metabolism as a key regulator of macrophage polarization and function. Pro-inflammatory M1 macrophages rely on glycolysis and produce high levels of reactive oxygen species (ROS) and cytokines, while reparative M2 macrophages depend on oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO). Mitochondrial dysfunction-characterized by excessive mitochondrial ROS (mtROS), impaired mitophagy, and disrupted fission/fusion dynamics-exacerbates immune dysregulation and tissue injury. Organ-specific macrophage metabolic reprogramming further influences sepsis pathology, particularly in the kidney, lung, and heart. Therapeutic strategies targeting mitochondrial pathways-such as small-molecule modulators, stem cell-derived extracellular vesicles, and RNA-based gene therapies-have shown promise in restoring macrophage homeostasis and improving outcomes. This review underscores the importance of immunometabolic regulation in sepsis and advocates for mitochondria-targeted interventions as a novel precision approach to immune modulation.

Keywords:  Immunometabolism; Macrophage polarization; Mitochondrial dysfunction; Mitophagy; Sepsis

DOI:  https://doi.org/10.1186/s40001-025-03590-4
Virology. 2025 Nov 29. pii: S0042-6822(25)00380-0. [Epub ahead of print]615 110766

Decoding the metabolic crosstalk between glycolysis and RNA viral pathogenesis.

Vijay Singh Bohara, Sachin Kumar.

  RNA viruses induce metabolic reprogramming in the host cells by shifting metabolism towards enhanced glycolysis, rapidly converting glucose to lactate, a phenomenon known as the Warburg effect. This metabolic shift supports viral replication by providing essential macromolecular precursors and energy. They regulate key components of glycolysis, including glucose transporters and glycolytic enzymes, to facilitate increased glucose uptake and its flux. Glycolysis is also crucial for the activation of immune cells and the regulation of cytokine production. This review summarises the molecular mechanisms driving these metabolic alterations to better understand the virus-host interactions. The factors regulating these mechanisms can be potential therapeutic targets for controlling viral infections.

Keywords:  Cytokines; Glucose transporters; Hypoxia-inducible factor; Interferons; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.virol.2025.110766
Sci Rep. 2025 Dec 01. 15(1): 42939

Mitochondrial glutathione transporter SLC25A40 regulates macrophage cytokine production.

Maureen Yin, Eva M Palsson-McDermott, Órlaith C Henry, Ziqian Ge, Juliana E Toller-Kawahisa, Yukun Min, Anne F McGettrick, Adam L Gordon, Stella B Heffernan, Laura Marrone, Bryan P Marzullo, Katherine L Eales, Sally A Clayton, Daniel A Tennant, Richard K Porter, Luke A J O'Neill.

  Mitochondrial glutathione (mtGSH) supports iron-sulfur cluster (ISC) stability in the electron transport chain (ETC). Here we have investigated the role of the mtGSH transporter SLC25A40 in macrophage activation. SLC25A40 is present in both murine and human macrophages and its expression was increased by LPS treatment. Reducing SLC25A40 expression using siRNA destabilized ISC-rich ETC proteins and elevated mitochondrial and cellular reactive oxygen species (ROS). It also induced expression of the genes Gclc and Gclm, which are involved in GSH biosynthesis. SLC25A40 deficiency also diminished IL-1β and IL-10 production at the transcriptional level in response to LPS. As a result, the production of mature IL-1β was decreased following activation of NLRP3 by nigericin or ATP, with no effect on pyroptosis. Depleting mtGSH with mitochondrially-targeted CDNB phenocopied these defects, whereas supplementation with a cell-permeable GSH ester partially restored pro-IL-1β production. Together, these data identify SLC25A40 as a key regulator that sustains ETC integrity to promote cytokine production, revealing a previously unrecognized role for the SLC25A40-mtGSH axis in coupling mitochondrial redox control to macrophage activation.

Keywords:  Cytokine; Electron transport chain (ETC); Glutathione (GSH); Macrophage immunometabolism; Mitochondria; SLC25A39/40

DOI:  https://doi.org/10.1038/s41598-025-30333-6
Precis Clin Med. 2025 Dec;8(4): pbaf025

Metabolic regulation of T cell production of IL-10 and IL-22 protects against intestinal inflammation.

Han Liu, Xiaojing Zhao, Tianming Yu, Yu Yu, Suxia Yao, Wenjing Yang, Yingzi Cong.

   Objectives: Inflammatory bowel disease is driven by dysregulated CD4⁺ T cell responses to the intestinal microbiota. While T cells can exacerbate inflammation by producing proinflammatory cytokines, they also produce anti-inflammatory mediators, such as interleukin 10 (IL-10) and IL-22. However, the metabolic programs that regulate IL-10 and IL-22 production remain incompletely defined.
Methods: We used CBir1 transgenic mice and in vitro Th1 polarization assays to investigate how metabolic pathways regulate T cell production of IL-10 and IL-22. A panel of metabolic inhibitors was tested for their effects on cytokine expression. Transcriptional mechanisms were assessed using bulk RNA sequencing, qPCR, Enzyme-linked immunosorbent (ELISA), and CRISPR-Cas9-mediated gene editing. Functional relevance was validated using Citrobacter rodentium infection and T cell suppression assays in vivo and in vitro.
Results: Among tested metabolic inhibitors, dichloroacetate (DCA) significantly enhanced IL-10 and IL-22 production by CD4⁺ T cells. DCA increased maximal oxygen consumption and decreased lactate secretion in T cells. Mechanistically, DCA upregulated aryl hydrocarbon receptor (Ahr) and downregulated Bhlhe40, without affecting Prdm1. Pharmacologic inhibition of Ahr suppressed DCA-induced IL-22, but not IL-10, while Bhlhe40 knockout enhanced IL-10 production, identifying distinct transcriptional regulators for each cytokine. Functionally, DCA-treated Th1 cells suppressed naïve T cell proliferation via IL-10. In an in vivo experiment, DCA treatment protected mice from C. rodentium-induced colitis.
Conclusions: Our findings demonstrate that DCA enhances IL-22 and IL-10 production in Th1 cells through Ahr and Bhlhe40, respectively. These results identify a novel metabolic mechanism by which DCA promotes mucosal immune regulation and highlight its potential as a therapeutic strategy for inflammatory bowel disease.

Keywords:  Ahr; Bhlhe40; IL-10; IL-22; T cell metabolism; dichloroacetate

DOI:  https://doi.org/10.1093/pcmedi/pbaf025
Front Cell Infect Microbiol. 2025 ;15 1730767

Editorial: Exploring macrophage metabolic adaptations to bacterial infection: pathways and immune responses.

Marc Herb, Alexander Gluschko, Raja Ganesan, Nirmal Robinson.



Keywords:  antioxidative responses; bacterial infection; immunometabolism; keyword; macrophages

DOI:  https://doi.org/10.3389/fcimb.2025.1730767
J Immunol. 2025 Dec 03. pii: vkaf310. [Epub ahead of print]

Restriction of IgA secretion in gut plasma cells is driven by a tissue-specific glycolytic program.

Victoria Zoccoli-Rodriguez, John D Iwaniec, Joel R Wilmore.

  IgA-secreting plasma cells (PCs) provide durable humoral immunity by supplying critical antibodies to mucosal and systemic sites. These cells are found in large numbers in the gut lamina propria and the bone marrow (BM). In this study, we found that IgA+ PCs in the gut secrete significantly fewer antibodies on a per-cell basis compared to BM PCs in B6 mice. While the cell-intrinsic and -extrinsic signals responsible for regulating BM PC function have been extensively studied, these regulatory signals are understudied in gut PCs. Recent studies have established that metabolism is a critical component to optimized PC function in the BM. To evaluate the metabolic pathways utilized by tissue-resident IgA+ PCs, we utilized the flow cytometry-based SCENITH assay and determined that gut IgA+ PCs have increased glycolytic capacity, in contrast to increased mitochondrial dependency in BM IgA+ PCs. Consistent with a glycolytic phenotype, gut IgA+ PCs have a high capacity to uptake glucose, high mTORC1 activity, and low cellular reactive oxygen species. To determine if glycolysis is restricting gut IgA+ PCs' antibody secretion, we used inhibitors to target key bioenergetic pathways. We found that antibody secretion is enhanced by inhibiting the switch to glycolysis, and conversely restricted when PCs are prevented from utilizing oxidative phosphorylation. Herein, we identified that tissue-specific metabolic programs regulate PC function, where glycolysis restricts antibody secretion in the gut. Understanding how function is regulated in tissue-resident PCs can be leveraged to optimize better antibody responses for maintaining intestinal homeostasis, targeting mucosal pathogens, and optimizing mucosal vaccines.

Keywords:  B cells; antibodies; metabolism; mucosa

DOI:  https://doi.org/10.1093/jimmun/vkaf310
Trends Immunol. 2025 Dec 01. pii: S1471-4906(25)00285-6. [Epub ahead of print]

Glycolytic diversity drives immune complexity in cancer.

Cai-Yuan Wu, Chun-Xiang Huang, Yuan Wei, Dong-Ming Kuang.

  The interaction between the tumor immune microenvironment (TIME) and the tumor determines whether immune evasion or antitumor immunity prevails. Metabolic reprogramming is increasingly recognized as a critical factor shaping the tumor immune response. Glucose metabolism regulates the intrinsic cellular states of both immune and tumor cells, while simultaneously shaping the surrounding microenvironment. The glycolytic diversity of immune and tumor cells drives the complexity of the TIME. In this Review, we explore how glucose metabolism remodels the TIME and how these metabolic alterations influence immune effector function and immune evasion. We also highlight the potential for integrating microenvironmental modulation as a promising therapeutic strategy in glucose-targeted cancer therapies.

Keywords:  glucose metabolism; glucose metabolism-targeted therapies; tumor immune microenvironment

DOI:  https://doi.org/10.1016/j.it.2025.11.002
Virology. 2025 Nov 28. pii: S0042-6822(25)00378-2. [Epub ahead of print]615 110764

The roles of sugar metabolism mechanisms and metabolites in viral infections.

Jieyi He, Xianghong Ju, A M Abd El-Aty, Xiaoxi Liu, Xiaowen Li.

  Viral infections pose a persistent challenge to global health by triggering sophisticated molecular interactions and extensive metabolic reprogramming within host organisms. Glycolysis-a central energy metabolism pathway-is dynamically and bidirectionally regulated during infection, reflecting a continuous metabolic interplay between pathogen and host. Rather than maintaining a static metabolic state, glycolytic flux is shaped by competing demands: viruses actively stimulate glycolysis to support replication, while hosts suppress it as a defensive strategy. This regulatory balance shifts across distinct stages of infection-from viral entry and replication peaks to immune clearance-resulting in phase-specific fluctuations in glycolytic activity that reveal a dynamic metabolic tug-of-war. In this review, we synthesize current understanding of how viruses recurrently activate host glycolysis to enhance replication, detailing conserved mechanisms of metabolic hijacking and the multilayered counterstrategies employed by the host. We further evaluate emerging therapeutic approaches, including targeted glycolytic inhibitors and combined immunomodulatory regimens, while addressing challenges related to specificity and efficacy. Finally, we highlight promising research directions such as tissue-specific nanodelivery platforms and single-cell multi-omics integration, which together offer a conceptual framework for developing next-generation antiviral therapies.

Keywords:  Antiviral therapy; Glycolysis; Metabolic reprogramming; Viral infection

DOI:  https://doi.org/10.1016/j.virol.2025.110764
Nat Commun. 2025 Dec 04. 16(1): 10898

Cytochrome c oxidase dependent respiration is essential for T cell activation, proliferation and memory formation.

Tatiana N Tarasenko, Emily Warren, Bharati Singh, Amanda Fuchs, Jose Marin, Marten Szibor, Christopher King, Peter J McGuire.

T cell activation requires extensive metabolic reprogramming, but the specific requirement for mitochondrial respiration (MR) remains unresolved. While most studies have focused on aerobic glycolysis as the primary driver of proliferation and effector function, the role of MR has not been completely defined. To isolate MR from proton pumping by cytochrome c oxidase (COX), we expressed the non-proton-pumping alternative oxidase (AOX) in activated COX-deficient T cells. AOX restored electron flow, membrane potential, and mitochondrial ATP production, ultimately rescuing proliferation, effector and memory differentiation, and antiviral immunity. These improvements required upstream electron input, particularly from Complex I, with Complex II and DHODH contributing more modestly. Despite restored MR, glycolysis remained elevated, likely due to altered redox signaling. These findings demonstrate that MR, normally mediated by COX, is necessary and can be sufficient to support T cell activation and function, independent of proton translocation, provided upstream electron input is maintained.

DOI: https://doi.org/10.1038/s41467-025-65910-w
Sci Rep. 2025 Dec 03.

ApoA1-driven cholesterol efflux and macrophage polarization orchestrate T-cell differentiation towards controlling Leishmania donovani pathogenesis.

Vikash Kumar, Dayakar Alti, Shobha Kumari, Ravi Ranjan, Divya Prasad, Veer Singh, Abhik Sen, Pradeep Das, Krishna Pandey, Ashish Kumar.

  Lipid metabolism plays a decisive role in host-pathogen interactions and immune regulation, with apolipoproteins (Apo) being central to this process. However, their role in leishmaniasis remains unexplored. Herein, we deliberate the immunoregulatory function of ApoA1 during Leishmania donovani infection using THP-1-derived macrophages alone and in combination with T lymphocytes derived from human PBMC. We found low serum ApoA1 levels in active VL and PKDL than in healthy controls. It was shown that direct interaction of ApoA1 with ABCA1 (ATP-binding cassette transporter A1) on macrophages promotes cholesterol efflux, reflected by increased HDL levels and reduced total cellular cholesterol. This phenomenon was associated with reduced Leishmania infectivity and its downstream signaling in macrophages, i.e., downregulation of PPAR-γ and the endoplasmic reticulum-stress marker CHOP. Additionally, ApoA1 in the presence of extracellular HDL slightly promoted macrophage polarization towards M1, as indicated by increased expression of IL-12 and iNOS2 or nitric oxide production, alongside reduced expression of M2 phenotype-associated markers, including IL-10 and arginase. In co-culture with PBMC-derived T-cells, ApoA1-primed macrophages facilitated Th1 polarization, as demonstrated by increased IFN-γ and STAT1, and indirectly by reduced expression of Th2-specific markers (GATA-3 and IL-4). Overall, these results implicate ApoA1 as a vital immunomodulatory factor and potential therapeutic target in leishmaniasis.

Keywords:   Leishmania donovani ; Apolipoprotein A1; Cholesterol efflux; Human PBMCs; M1-macrophages; Th1-polarization

DOI:  https://doi.org/10.1038/s41598-025-30130-1
mSystems. 2025 Dec 04. e0150725

Co-culture metabolomics: a powerful tool for uncovering host-pathogen phenotypes driving Burkholderia infections.

Stephanie L Bishop.

  Melioidosis, caused by the soil-dwelling pathogen Burkholderia pseudomallei (Bt), is a severe respiratory infection with limited treatment options. To investigate the host-pathogen metabolic interplay occurring during these intracellular infections, Hicks et al. built upon an in vitro co-culture model they developed with airway epithelial cells and Bt as a surrogate pathogen (D. J. Hicks, N. Aiosa, A. Sinha, O. A. Jaiyesimi, et al., mSystems 10:e00611-25, 2025, https://doi.org/10.1128/msystems.00611-25). Using an untargeted metabolomics approach tailored to central metabolism, they identified several host pathways that were altered during the Bt infection: polyamine biosynthesis, nicotinamide adenine dinucleotide salvage, and the tricarboxylic acid cycle. In addition, they found that several bacterial metabolites, including methylated nucleotide bases, peptidoglycan precursors, and amino acid derivatives, were altered due to Bt infection. These results show that co-culture metabolomics is an effective strategy for identifying host-pathogen metabolic phenotypes resulting from bacterial infections and can uncover new therapeutic strategies to combat melioidosis.

Keywords:  Burkholderia; HILIC; LC-MS; airway epithelial cells; infection culture metabolomics; melioidosis

DOI:  https://doi.org/10.1128/msystems.01507-25
J Neuroinflammation. 2025 Dec 06.

SYK regulates Schwann cell metabolic reprogramming to promote axonal regeneration in immune-mediated neuropathy.

Nannan Zhang, Chen Liu, Fangyu Chen, Qian Zheng, Yuzhong Wang, Fangzhen Shan.

  Immune-mediated peripheral neuropathies like acute motor axonal neuropathy (AMAN) drive axonal degeneration through unresolved neuroinflammation, where Schwann cell (SC) metabolic reprogramming fails to support regeneration. While Spleen Tyrosine Kinase (SYK) is recognized for orchestrating immune responses and central glial function, its role in SC immunometabolism remains unknown. We identify SYK as a master regulator bridging neuroinflammation and SC metabolic adaptation in AMAN. SYK was compensatorily upregulated in SCs at sciatic nerve lesions following anti-GD1a IgG-mediated autoimmune injury, suggesting its activation is part of the protective response. Experimental SYK deficiency triggered catastrophic metabolic collapse, impairing glycolysis and oxidative phosphorylation via dysregulated PI3K/AKT/mTOR and HIF-1α/c-Myc signaling. This suppressed glucose uptake, glycolytic enzymes, mitochondrial biogenesis, and electron transport chains, exacerbating mitochondrial damage. Crucially, loss of this SYK response disrupted AMPK/STAT3-dependent mitophagy, causing ROS accumulation and mitochondria-dependent apoptosis, linking metabolic failure to glial degeneration. SYK deficiency further impaired neuro-glial metabolic coupling, reducing lactate production and MCT1-mediated transfer to axons, which compromised axonal bioenergetics. In vivo, targeted SYK knockdown in AMAN mice to block this endogenous upregulation amplified neuroinflammation, impaired nerve bioenergetics, exacerbated muscle atrophy, and worsened neurofunctional deficits. Mechanistically, SYK integrates immune-triggered metabolic reprogramming with mitochondrial quality control to fuel regeneration. These findings establish SYK as a pivotal upstream coordinator of SC metabolism and neuro-immunomodulation that enables metabolic support for axonal regeneration. Targeting SYK to enhance its activity represents a promising metabolic therapy for immune-mediated neuropathy.

Keywords:  Energy metabolism; Mitophagy; Peripheral nerve regeneration; Schwann cell; Spleen tyrosine kinase

DOI:  https://doi.org/10.1186/s12974-025-03624-y
Biochim Biophys Acta Mol Cell Res. 2025 Nov 27. pii: S0167-4889(25)00195-8. [Epub ahead of print]1873(2): 120090

Metabolic reprogramming is implicated in the differential response of the CAL-1 plasmacytoid dendritic cell line to autophagy inhibitors.

Carlota Ramalhinho, Paulo Antas, Philippe Pierre, Iola F Duarte, Catarina R Almeida.

  Plasmacytoid dendritic cells (pDCs) produce large amounts of type I Interferons (IFN) and pro-inflammatory cytokines, playing crucial roles in antiviral and anticancer immunity as well as in autoimmune diseases. Understanding the mechanisms that regulate pDC function is therefore essential. Autophagy, a process responsible for recycling intracellular components, influences cellular metabolism and modulates immune responses. Here, we used the human CAL-1 pDC cell line, a validated model for primary pDCs, to investigate the functional impact of autophagy inhibition and the contribution of metabolism to these effects. CAL-1 cells were treated with two autophagy inhibitors, Spautin-1 and VPS34-IN1, and cytokine production was assessed by RT-qPCR and ELISA, while cellular metabolism was analysed by untargeted metabolomics of cell extracts and of medium supernatants. VPS34-IN1, but not Spautin-1, induced robust expression of IFN-β and TNF-α. The two inhibitors also elicited distinct metabolic responses: Spautin-1 enhanced glycolysis, promoted an anabolic phenotype with increased utilization of amino acids, and upregulated mTOR signaling. In contrast, VPS34-IN1 decreased glycolysis, increased intracellular amino acids, reduced TCA intermediates, and induced energy stress, reflected by an increased AMP/(ADP + ATP) ratio and decreased NAD+. These changes were consistent with AMPK activation, and pharmacological inhibition of AMPK with dorsomorphin (compound C) abolished cytokine production in VPS34-IN1-treated cells. Together, these results indicate that differential cytokine responses to autophagy inhibition are driven primarily by metabolic rewiring rather than autophagic flux per se, highlighting the interplay between metabolism, mitochondrial ROS, and signaling pathways in pDC activation.

Keywords:  AMPK; Cytokine production; Glycolysis; Metabolomics; Spautin-1; VPS34-inhibitor 1; mTOR

DOI:  https://doi.org/10.1016/j.bbamcr.2025.120090
Res Sq. 2025 Nov 19. pii: rs.3.rs-7983397. [Epub ahead of print]

Dietary Polyunsaturated Fatty Acids Regulate Dendritic Cell Function via Nrf2-dependent Control of Ferroptosis.

Juan Cubillos-Ruiz, Deepika Awasthi, Erin McMinn, Camilla Salvagno, Sung-Min Hwang, Tito Sandoval, Chang-Suk Chae, Wiam Madani, Jacqueline Crater, Kaushik Sen, Daniel Min, Alexander Emmanuelli, Chen Tan, Andrew Dannenberg, Diana Morales, Evelyn Cantillo, Eloise Chapman-Davis, William Zhang, Suzanne Cloonan.

Dendritic cells (DCs) orchestrate adaptive immune responses to pathogens and tumors, yet how dietary lipids influence DC metabolism and function remains largely unexplored. Here we show that dietary polyunsaturated fatty acids (PUFAs) govern DC activity via Nuclear factor erythroid 2-like 2 (Nrf2)-dependent control of ferroptosis. In mice, an n-6 PUFA-enriched diet suppressed DC Nrf2 signaling, depleted glutathione, and induced lipid peroxidation and ferroptosis, thereby compromising antigen presentation. By contrast, dietary n-3 PUFAs enhanced Nrf2 signaling and redox homeostasis, preserving DC integrity and T cell priming. Pharmacologic Nrf2 activation or ferroptosis inhibition restored the function of DCs from n-6 PUFA-fed mice. Notably, adoptive immunotherapy with DCs conditioned by a diet rich in n-3 PUFAs-but not n-6 PUFAs-elicited durable, T cell-dependent control of metastatic ovarian cancer. These findings identify dietary PUFAs as key modulators of the Nrf2-glutathione-ferroptosis axis in DCs and reveal a redox-sensitive metabolic checkpoint that can be leveraged to improve cancer immunotherapy.

DOI: https://doi.org/10.21203/rs.3.rs-7983397/v1
Cell Mol Gastroenterol Hepatol. 2025 Nov 28. pii: S2352-345X(25)00224-3. [Epub ahead of print] 101683

The glutamine metabolic switch influences the response of neonatal intestinal macrophages to breast milk.

Xu Han, Yutong Hou, Taoying Chen, Zhenyu Jia, Fuqiang Yuan, Mingxin Wang, Yinling Su, Ru Yan, Xiaolei Wang, Weilai Jin, Yahui Zhou, Yun Li, Le Zhang.

   BACKGROUND & AIMS: Breast milk contains abundant glutamine and glutamate, yet their roles in neonatal gut health remain controversial. We aimed to investigate how these amino acids influence neonatal enteritis and the underlying mechanisms.
METHODS: We used a neonatal rat necrotizing enterocolitis (NEC) model to test the effects of glutamine and glutamate given either before disease onset or during NEC progression. Previously published human neonatal NEC scRNA-seq data were reanalyzed to assess immune cell composition and pathway activity. Bone marrow-derived macrophages (BMDMs) were used to examine inflammatory responses in vitro. Flow cytometry and transcriptomics were applied to analyze metabolic reprogramming of ileal macrophages.
RESULTS: Glutamine and glutamate prevented NEC when administered prophylactically but worsened disease when given during NEC progression. scRNA-seq revealed enrichment of macrophages with activated inflammatory pathways in NEC ileum. In vitro, pretreatment with glutamine or glutamate reduced lipopolysaccharide-induced cytokine expression in BMDMs, whereas administration after stimulation had no benefit. In vivo, glutamine pretreatment decreased CD45+F4/80+CD11b/c+TNFα+ macrophages, while treatment during NEC increased this subset. Integrated analyses showed NEC upregulated glutaminase (GLS) and downregulated glutamate dehydrogenase (GLUD1) in ileal macrophages. Pretreatment with glutamine or glutamate restored GLUD1 expression, favoring α-ketoglutarate (α-KG) rather than succinate metabolism. Supplementation with α-KG reversed glutamine-induced macrophage activation during NEC, whereas succinate abolished the protective effect of glutamine pretreatment.
CONCLUSIONS: Glutamine and glutamate exert dual, context-dependent effects in neonatal enteritis by modulating macrophage glutamine metabolism. These findings provide mechanistic insight and suggest a basis for personalized glutamine supplementation strategies in neonatal gut disorders.

Keywords:  breast milk; glutamine metabolism; macrophage; necrotizing enterocolitis

DOI:  https://doi.org/10.1016/j.jcmgh.2025.101683
Cell. 2025 Nov 28. pii: S0092-8674(25)01251-6. [Epub ahead of print]

Innate immune and metabolic signals induce mitochondria-dependent membrane lysis via mitoxyperiosis.

Yaqiu Wang, Jianlin Lu, Alexandre F Carisey, Sangappa B Chadchan, Ha Won Lee, R K Subbarao Malireddi, Bhesh Raj Sharma, Nagakannan Pandian, Rebecca E Tweedell, Gustavo Palacios, Nathalie Becerra Mora, Camenzind G Robinson, Aaron Pitre, Peter Vogel, Taosheng Chen, Michael P Murphy, Thirumala-Devi Kanneganti.

  The combination of innate immune activation and metabolic disruption plays critical roles in many diseases, often leading to mitochondrial dysfunction and oxidative stress that drive pathogenesis. However, mechanistic regulation under these conditions remains poorly defined. Here, we report a distinct lytic cell death mechanism induced by innate immune signaling and metabolic disruption, independent of caspase activity and previously described pyroptosis, PANoptosis, necroptosis, ferroptosis, and oxeiptosis. Instead, mitochondria undergoing BAX/BAK1/BID-dependent oxidative stress maintained prolonged plasma membrane contact, leading to local oxidative damage, a process we termed mitoxyperiosis. This process then caused membrane lysis and cell death, termed mitoxyperilysis. mTORC2 regulated the cell death, and mTOR inhibition restored cytoskeletal activity for lamellipodia to retract and mobilize mitochondria away from the membrane, preserving integrity. Activating this pathway in vivo regressed tumors in an mTORC2-dependent manner. Overall, our results identify a lytic cell death modality in response to the synergism of innate immune signaling and metabolic disruption.

Keywords:  carbon starvation; cytokine; inflammasome; inflammatory cell death; innate immunity; mTOR; metabolism; mitochondria; oxidative damage; tumor

DOI:  https://doi.org/10.1016/j.cell.2025.11.002
J Transl Med. 2025 Dec 05. 23(1): 1383

UBE2S-mediated deubiquitination of GLUT1 via USP10 regulates glucose metabolic reprogramming and immune microenvironment to promote fibrosis in endometriosis.

Baoju Wang, Li Hu, Zhen Zhang, Yue Yin, Linyao Zheng, Han Wu, Yan Cheng, Guangmei Zhang.

   BACKGROUND: Endometriosis (EM) is a chronic inflammatory disorder characterized by the growth of ectopic endometrial-like tissue and fibrosis. Metabolic reprogramming, particularly enhanced glycolysis, and immune microenvironment dysregulation are key features of EM progression. However, the underlying molecular mechanisms remain poorly understood.
METHODS: This study integrated transcriptomic analysis, immunoprecipitation-mass spectrometry (IP-MS), co-immunoprecipitation, and ubiquitination assays to systematically investigate the role of Ubiquitin-Conjugating Enzyme E2S (UBE2S) in regulating glucose metabolism and immune modulation in EM. In vitro, cell experiments, and mouse models were used to validate its effects on glycolysis, macrophage polarization, and fibrosis.
RESULTS: UBE2S was significantly upregulated in ectopic endometrial stromal cells. IP-MS analysis identified glucose transporter 1 (GLUT1) and Ubiquitin-Specific Peptidase 10 (USP10) as key interacting proteins of UBE2S. Mechanistic studies revealed that UBE2S mediates K48-linked deubiquitination of GLUT1 through USP10, stabilizing GLUT1 protein and enhancing glycolytic activity. This metabolic reprogramming leads to lactate accumulation, which induces M2 macrophage polarization and secretion of transforming growth factor β1 (TGF-β1), thereby promoting fibroblast-to-myofibroblast transition and accelerating fibrosis in the lesions. The UBE2S inhibitor cephalomannine significantly downregulated GLUT1 expression, inhibited glycolysis, blocked M2 polarization, and alleviated fibrosis in ectopic lesions.
CONCLUSION: This study reveals the molecular mechanism by which the UBE2S-USP10-GLUT1 axis regulates the immune microenvironment and promotes fibrosis in EM through metabolic reprogramming. Our findings provide new insights into the pathogenesis of EM and offer a theoretical basis for targeting UBE2S in therapeutic strategies.

Keywords:  Endometriosis; Fibrosis; GLUT1; Glycolysis; M2 macrophage polarization; UBE2S; USP10

DOI:  https://doi.org/10.1186/s12967-025-07436-9
Adv Sci (Weinh). 2025 Dec 05. e11595

ETV1 Drives CD4+ T Cell-Mediated Intestinal Inflammation in Inflammatory Bowel Disease Through Amino Acid Transporter Slc7a5.

Yan Shi, Song Wang, Yuqing Yan, Wei Chen, Yingying Cao, Dafan Chen, Wei Chen, Caiyun Ma, Xinjian Wan.

  Excessive CD4+ T cell responses drive inflammatory bowel disease (IBD), yet the transcriptional mechanisms underlying their dysfunction remain incompletely understood. Here, it is demonstrated that E-twenty-six variant transcription factor 1 (ETV1) is upregulated in IBD patients and positively correlates with disease severity. Etv1 deficiency impairs CD4+ T cell activation, proliferation, and T helper 17 (Th17) cell differentiation, thereby ameliorating TNBS-induced colitis. Moreover, Etv1 deficiency attenuates CD45RBhighCD4+ T cell-induced colitis, characterized by a reduction in pathogenic CD4+ T cells in the intestinal mucosa. Pharmacological inhibition of ETV1 ameliorates colitis in recombination activating gene 1-deficient mice and suppresses human IBD T cell responses ex vivo. Mechanistically, Etv1 binds to the promoter of the gene encoding the amino acid transporter solute carrier family 7 member 5 (Slc7a5), enhancing its expression and subsequent amino acid uptake to fuel T cell pathogenicity. Restoring Slc7a5 expression rescues the proliferation, differentiation, and colitogenic function of Etv1-deficient CD4⁺ T cells. Clinically, SLC7A5 is upregulated in IBD, and its blockade ameliorates T cell-driven colitis in vivo. Collectively, the results establish a critical role for the ETV1-Slc7a5 axis in driving pathogenic CD4⁺ T cell responses in IBD, highlighting this pathway as a novel therapeutic target.

Keywords:  ETV1; SLC7A5; Th17; inflammatory bowel diseases

DOI:  https://doi.org/10.1002/advs.202511595
Cell Rep. 2025 Dec 04. pii: S2211-1247(25)01416-0. [Epub ahead of print]44(12): 116644

Quiescent ILC1 cells confer protection against MCMV infection during undernutrition.

Megumi Tatematsu, Shunsuke Takasuga, Akane Fuchimukai, Shinsuke Seki, Guangwei Cui, Takuma Asahi, Atsushi Hirao, Veronika Sexl, Tsukasa Nabekura, Akira Shibuya, Koichi Ikuta, Takashi Ebihara.

  In the liver, group 1 innate lymphoid cells (ILCs) comprise 10%-20% tissue-resident ILC1 cells and 80%-90% conventional natural killer (NK) cells. Both cell types contribute to early defense against virus infection by secreting interferon γ (IFN-γ). However, the distinct role of ILC1 cells in viral infection remains incompletely understood. Here, we identify that ILC1 cells outnumber NK cells, constituting 80%-90% of group 1 ILCs in the liver during undernutrition. Mechanistically, undernutrition significantly reduces NK cell numbers, while hepatic ILC1 cells enter a quiescent state that allows them to survive in an mTORC1-dependent manner. Metabolically, quiescent ILC1 cells exhibit greater glucose uptake than NK cells and efficiently utilize it via oxidative phosphorylation, which is induced by mTORC1. Finally, ILC1-deficient mice succumb to murine cytomegalovirus (MCMV) infection under undernourished conditions but not when fed ad libitum. These findings suggest a non-redundant function of hepatic ILC1 cells in protecting the host against MCMV infection during undernutrition.

Keywords:  CP: Immunology; CP: Metabolism; IFN-γ; ILC1; MCMV; NK; OXPHOS; mTORC1; quiescence; undernutrition

DOI:  https://doi.org/10.1016/j.celrep.2025.116644
Front Immunol. 2025 ;16 1682846

Comprehensive analysis of metabolism-related genes in sepsis reveals metabolic-immune heterogeneity and highlights GYG1 as a potential therapeutic target.

Jie Zheng, Kangjie Qin, Xiaoqin Wang, Banghai Feng, Yuting Zhang, Yiyu Wang, Han Qin, Qiuyu Dai, Xinxin Liu, Kun Yu, Song Qin.

   Background: Sepsis is a life-threatening syndrome characterized by dysregulated host immune responses, yet the metabolic drivers of immune dysfunction remain poorly understood.
Methods: Here we systematically profiled metabolism-related genes (MRGs) in sepsis using bulk transcriptomic data and stratified patients into two subgroups with distinct immune infiltration profiles by MRGs, as assessed by CIBERSORT and single-cell RNA-seq integration. Machine learning identified five hub metabolic genes for constructing a metabolic risk score, whose prognostic relevance was robustly validated in an external cohort. Single cell analyses, cell-cell communication, and cell-type-specific differential expression analyses were performed to dissect the immunological context. Finally, in vivo validation was conducted using an LPS-induced sepsis mouse model.
Results: Patients in the high metabolic risk group exhibited a neutrophil-dominant and lymphocyte-suppressed immune landscape, consistent across bulk and single-cell analyses. Among the five hub genes (ALPL, CYP1B1, GYG1, OLAH, VNN1), GYG1 demonstrated the strongest predictive performance and was highly expressed in monocytes, neutrophils, and proliferating myeloid cells. High-risk patients displayed intensified monocyte-dendritic cell interactions and transcriptional programs enriched in neutrophil degranulation pathways. In vivo, Gyg1 was markedly upregulated in septic mice, and LNP-mediated siRNA knockdown of Gyg1 significantly improved survival in the LPS model. Mechanistically, Gyg1 knockdown significantly reduced glycogen content in myeloid cells, attenuated IL-6 and TNF-α production, alleviated LPS-induced neutrophil, and modestly decreased CD40 expression in monocytes and dendritic cells. These results collectively suggest that Gyg1 regulates metabolic fueling of inflammatory activation and intercellular communication during sepsis.
Conclusions: This integrative multi-omics study established a robust immune-metabolic risk score system to predict sepsis patient outcomes and identified GYG1 as a metabolic driver of innate immune hyperactivation. Targeting GYG1 via LNP-siRNA delivery reduces glycogen availability and inflammatory output in myeloid cells, mitigating immune overactivation and improving disease outcomes in vivo, thereby highlighting its potential as a novel therapeutic target for sepsis.

Keywords:  GYG1; immune infiltration; lipid nanoparticles; metabolism; risk score; sepsis

DOI:  https://doi.org/10.3389/fimmu.2025.1682846
Front Physiol. 2025 ;16 1666999

Activation of the pentose phosphate pathway by microcurrent stimulation mediates antioxidant effects in inflammation-stimulated macrophages.

Mikiko Uemura, Noriaki Maeshige, Atomu Yamaguchi, Xiaoqi Ma, Yunfei Fu, Taketo Inoue, Mami Matsuda, Yuya Nishimura, Tomohisa Hasunuma, Ji Wang, Hiroyo Kondo, Hidemi Fujino.

   Introduction: Excessive inflammatory responses in macrophages lead to increased oxidative stress, and the excessive production of reactive oxygen species (ROS) causes tissue damage, contributing to the development of chronic diseases and tissue deterioration. Therefore, controlling the inflammatory response and ROS production is crucial for human health. Electrical stimulation (ES) has been shown to have antioxidant and anti-inflammatory effects on macrophages. However, the key pathway underlying these effects remains unclear.
Methods: In this study, ES was applied to Lipopolysaccharide (LPS)-stimulated macrophages, and the production of ROS and 8-hydroxy-2'-deoxyguanosine (8-OHdG), inflammatory cytokine expression, and intracellular metabolites were analyzed in a glucose-6-phosphate dehydrogenase (G6PD) knockdown experiment, the rate-limiting enzyme of the Pentose Phosphate Pathway(PPP).
Results: ES significantly increased sedoheptulose 7-phosphate (S7P), an intermediate metabolite in PPP, and reduced ROS and 8-OHdG production and the expression of inflammatory cytokines in LPS-stimulated macrophages. Meanwhile, ES did not exert antioxidant effects in G6PD-knockdown macrophages.
Discussion: These findings indicate that the antioxidant effects of ES are mediated by PPP in LPS-stimulated macrophages.

Keywords:  NADPH; glucose metabolism; macrophage; microcurrent stimulation; oxidative stress; pentose phosphate pathway (PPP)

DOI:  https://doi.org/10.3389/fphys.2025.1666999
Proc Natl Acad Sci U S A. 2025 Dec 09. 122(49): e2516288122

Oxidative pentose phosphate pathway is required for T cell activation and antitumor immunity.

Zihong Chen, Kellen L Olszewski, Rolf-Peter Ryseck, Xincheng Xu, Jacob A Boyer, Christian G Peace, Yihui Shen, Caroline R Bartman, Lydia Lynch, Joshua D Rabinowitz.

  Glucose is catabolized by two major metabolic pathways, glycolysis and the oxidative pentose phosphate pathway (oxPPP). The oxPPP generates nicotinamide adenine dinucleotide phosphate (NADPH) at two steps, glucose-6-phosphate dehydrogenase (G6PD), the most common enzyme deficiency in humans, and 6-phosphogluconate dehydrogenase (PGD). Previous literature suggests that G6PD supports but PGD limits T cell-mediated immunity. Here, we use T cell-specific knockout mouse models to show that both enzymes are required for antitumor immunity and response to immunotherapy. PGD knockout depletes mature T cells systemically, while G6PD loss does not reduce basal T cell populations but results in apoptosis upon activation. Such apoptosis is not reversed by major downstream products of the oxPPP, including antioxidants, nucleosides, or fatty acids. Instead, T cells are partially rescued by removal of media cystine, whose reduction requires NADPH. G6PD loss induces an oxidative stress response that upregulates cystine import, which together with low NADPH leads to fatal disulfide stress. Overall, these results highlight an essential role for the oxidative pentose phosphate pathway in cystine homeostasis and T cell-mediated immunity.

Keywords:  NADPH; T cell activation; T cell antitumor immunity; disulfide stress; oxidative pentose phosphate pathway

DOI:  https://doi.org/10.1073/pnas.2516288122
J Transl Med. 2025 Nov 29.

Lactylation at the crossroads of immune metabolism and epigenetic regulation: revealing its role in rheumatic immune diseases.

Ziheng Zhu, Chuanbing Huang, Junjie Chen, Lei Wan, Chuanwei Zhang, Jianing Wang.

   BACKGROUND: Lactate was traditionally regarded as merely the end product of glycolysis; however, recent discoveries of lactylation have revealed that lactate can also directly serve as a substrate for epigenetic modification, filling a critical gap in the understanding of "metabolite-epigenetic regulation." In rheumatic immune diseases such as rheumatoid arthritis and systemic lupus erythematosus, the affected tissues, including the joint synovium and internal organs, are typically hypoxic. These regions demonstrate pronounced inflammatory infiltration and metabolic reprogramming, leading to the accumulation of lactate within the local microenvironment. In this context, lactylation directly links the metabolic state (lactate levels) of the microenvironment with epigenetic regulation of gene expression. This offers valuable insights into how metabolic cues specifically modulate the functions of immune cells, including polarization, activation, and cytokine secretion, as well as the behavior of tissue-resident cells, such as synovial fibroblasts. Conventional immunosuppressants demonstrate limited efficacy in correcting such metabolic abnormalities; thus, exploring novel mechanisms and therapeutic targets at the intersection of metabolism and epigenetics is urgently needed. Investigating the mechanistic role of lactylation, therefore, represents a crucial step toward developing innovative therapies for rheumatic autoimmune disorders.
METHODS: This review systematically summarizes the pivotal functions of lactylation within the immune-metabolic and epigenetic regulatory networks, examining its influence on metabolic pathways, chromatin modification, and disease progression. Furthermore, it discusses the modulatory roles of lactylation in immune cell activity, signaling pathway activation, and the generation of disease-specific modification patterns.
RESULTS: In summary, current evidence indicates that lactylation serves as a molecular bridge connecting "immunometabolism-epigenetic dysregulation-chronic inflammation." Its tissue specificity and diverse modification substrates contribute to a complex regulatory network. Therefore, targeting the lactylation regulatory axis may enable the conversion of pathological metabolic features into therapeutic opportunities.
CONCLUSION: Future research should emphasize single-cell lactylome profiling and the development of tissue-specific delivery systems to elucidate better and control the dual physiological and pathological functions of lactylation.

Keywords:  Epigenetic regulation; Immune diseases; Immune metabolism; Lactylation; Metabolic reprogramming; Rheumatic diseases

DOI:  https://doi.org/10.1186/s12967-025-07498-9
Nat Commun. 2025 Nov 29.

mTORC1 signaling in group 2 innate lymphoid cells coordinates neuro-immune crosstalk in allergic lung inflammation.

Dongdi Wang, Lin Hu, Jinyu Chen, Jinxin Qiu, Yue Chen, Michelle Zhang, Linfeng Zhao, Xiaohui Su, Jiping Sun, Ju Qiu, Wei Tang, Wenyong Zhou, Lei Shen.

Group 2 innate lymphoid cells (ILC2) initiate pathologic type 2 inflammation in allergic asthma in response to diverse tissue-derived stimuli. However, the molecular mechanisms by which ILC2 cells integrate and respond to environmental signals are unclear. Here, we show in a mouse model that in allergic asthma, mechanistic target of rapamycin complex 1 (mTORC1) activation in lung ILC2 cells increases. Genetic ablation of Raptor, an obligatory component of mTORC1 complex, results in reduced IL-5 and IL-13 production in ILC2 cells and protects mice from allergic inflammation. Pharmacological inhibition of mTORC1 by rapamycin suppresses ILC2 activation and ameliorates allergic lung inflammation. Mechanistically, mTORC1 activation upregulates neuromedin U receptor 1 (NMUR1) expression through epigenetic reprogramming, which augments ILC2 activation in response to neuromedin U (NMU). However, our experiments suggest that NMUR1 is not an exclusive mediator of ILC2 activation downstream of mTORC1. In conclusion, our work reveals that in ILC2s, mTORC1 signaling coordinates neuro-immune crosstalk for optimal activation, and highlights mTORC1 as a potential therapeutic target for allergic asthma.

DOI: https://doi.org/10.1038/s41467-025-66683-y
Hepatol Int. 2025 Dec 02.

Positive feedback between histone H4K16 lactylation and glycolysis promotes MAFLD progression.

Qinlian Jiao, Yidan Ren, Xiaoyu Teng, Maoxiao Feng, Xiaoyan Liu, Yuxuan Cai, Tangbin Hu, Mo Wang, Yunshan Wang.

   BACKGROUND/AIMS: Metabolic-associated fatty liver disease (MAFLD) is a progressive metabolic disorder characterized by hepatic steatosis, inflammation, and fibrosis. Emerging evidence suggests that lactate-driven histone lactylation may contribute to its pathogenesis, but mechanisms remain unclear.
METHODS: C57BL/6 mice were fed HFD or CDHFD, and hepatocytes were treated with OAPA. Histone lactylation was assessed by IF and WB. CUT&Tag and RNA-seq identified downstream targets, while H4K16R mutation, PDK4 knockdown, and dichloroacetic acid (DCA) inhibition were applied in vitro and in vivo.
RESULTS: Histone lactylation, especially H4K16la, was elevated in murine and human MASH and correlated with steatosis, inflammation, and fibrosis. H4K16la directly activated PDK4 transcription, forming a lactate-H4K16la-PDK4 feedback loop that exacerbated MAFLD. Genetic or pharmacologic inhibition reduced lactate, lipid accumulation, and liver injury.
CONCLUSIONS: We identify a lactate-H4K16la-PDK4 axis that drives metabolic reprogramming and MAFLD progression. Targeting PDK4 may represent a therapeutic strategy for MAFLD/MASH.

Keywords:  Glycolysis; Histone lactylation; Lactate; MAFLD; PDK4

DOI:  https://doi.org/10.1007/s12072-025-10978-1
iScience. 2025 Nov 21. 28(11): 113790

SIRT3 regulates PDHA1 acetylation in HUVECs to modulate inflammation and pyroptosis under clinorotation.

Min Jiang, Junjie Shao, Kun Lin, Lejian Lin, Shuai Yue, Haojie Yan, Jingjing Zhou, Shujin Shi, Xin Li, Ran Zhang.

  Microgravity-induced endothelial inflammation contributes to cardiovascular dysfunction in astronauts, but the metabolic mechanisms involved are not fully defined. Sirtuin-3 (SIRT3), a mitochondrial deacetylase, regulates cellular metabolism and redox balance. The results demonstrate that two-dimensional clinorotation-induced simulated microgravity suppresses SIRT3 in human umbilical vein endothelial cells (HUVECs), resulting in mitochondrial dysfunction, NLRP3 inflammasome activation, and pyroptosis. SIRT3 overexpression mitigated these effects, while SIRT3 knockdown exacerbated them. Mechanistically, SIRT3 deletion promoted acetylation of pyruvate dehydrogenase E1α (PDHA1) at lysine 83, inhibiting pyruvate dehydrogenase complex (PDHC) activity and shifting metabolism toward higher levels of glycolysis. PDHA1 transfection suppressed NLRP3 inflammasome activation, pyroptosis, and glycolysis in HUVECs under simulated microgravity, while restoring mitochondrial membrane potential (ΔΨm) and oxidative phosphorylation. The PDHA1-K83R mutant provided stronger protection than wild-type PDHA1. These findings reveal that the SIRT3-PDHA1 axis links mitochondrial metabolism to endothelial inflammation under simulated microgravity, suggesting that targeting this pathway could help maintain vascular health during spaceflight.

Keywords:  cell biology; microgravity sciences

DOI:  https://doi.org/10.1016/j.isci.2025.113790
Res Sq. 2025 Nov 20. pii: rs.3.rs-8036170. [Epub ahead of print]

Loss of Nuclear TDP-43 Impairs Lipid Metabolism in Microglia-Like Cells.

Khushbu Kabra, Dallin Dressman, Ryan Talcoff, Maedot Yidenk, Olivia M Rifai, Benjamin N Hoover, Neil A Shneider, Wassim Elyaman, Estela Area-Gomez, Elizabeth M Bradshaw.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease marked by progressive motor neuron loss, with TDP-43 pathology present in over 90% of cases. While neuroinflammation is a recognized hallmark, the role of microglia in ALS pathogenesis remains incompletely understood. Here, we demonstrate that TDP-43 regulates microglial function via triglyceride metabolism. Using shRNA-mediated TARDBP knockdown in human monocyte-derived microglia-like cells (MDMi), we observed suppressed cholesterol biosynthesis, upregulated fatty acid uptake, lipid droplet accumulation, enhanced phagocytic activity, and increased IL-1β production. Inhibiting diacylglycerol acyltransferase (DGAT) enzymes reduced lipid droplet formation, phagocytosis, and IL-1β, directly linking the triglyceride pathway to microglial activation. Patient-derived MDMi from both sporadic and TARDBP -mutant ALS cases showed overlapping as well as distinct alterations, some of which were reversed by DGAT inhibition. Our findings identify dysregulated triglyceride metabolism as a novel pathway through which TDP-43 mediates microglial dysfunction, highlighting a potential therapeutic target for ALS.

DOI: https://doi.org/10.21203/rs.3.rs-8036170/v1
Cell Death Discov. 2025 Dec 03.

USP5 promotes glycolysis of fibroblast-like synoviocytes by stabilizing the METTL14/m6A/GLUT1 axis in rheumatoid arthritis.

Xuan'an Li, Min Ling, Zhongchi Wen, Chonghua Jiang, Xiaohua Tan.

Fibroblast-like synoviocytes (FLSs) contribute to the advancement of rheumatoid arthritis (RA) through enhanced metabolic reprogramming. This research focused on exploring the role and underlying mechanism of ubiquitin-specific protease 5 (USP5) in modulating the glycolysis and activation of RA-FLSs. Here, we identified that knockdown of USP5 in RA rats reduced synovial inflammation and glycolytic activity, as evidenced by decreased serum lactate levels and GLUT1 expression. In RA-FLSs, USP5 knockdown or treatment with 2-DG reduced cell proliferation, migration, invasion, cytokine production, and glycolysis, while increased apoptosis. Mechanistically, USP5 stabilized METTL14 by inhibiting its ubiquitination, while METTL14 enhanced the m6A modification of GLUT1 mRNA, thereby increasing its expression. Furthermore, overexpression of METTL14 partially reversed the effects of USP5 knockdown on glycolysis and inflammatory activation in RA-FLSs. Additionally, knockdown of METTL14 inhibited RA-FLS glycolysis and inflammatory activation by downregulating GLUT1. Collectively, USP5 stabilized METTL14-mediated m6A modification of GLUT1 by inhibiting the ubiquitination of METTL14, thereby enhancing glycolysis and inflammatory activation in RA-FLSs. These results suggest that the USP5/METTL14/GLUT1 axis could be a potential therapeutic target for RA.

DOI: https://doi.org/10.1038/s41420-025-02890-2
Front Immunol. 2025 ;16 1698285

Regulatory T cell transdifferentiation as a driver of obesity and diabetes.

Acelya Yilmazer, Dimitra Maria Zevla, Karsten Kretschmer.

  Foxp3+ regulatory T (Treg) cells exhibit remarkable plasticity, enabling them to phenotypically and functionally adapt to diverse immune responses across tissues. However, this plasticity comes with the risk of lineage instability, including downregulation of Foxp3 and acquisition of pro-inflammatory effector programs. Although Treg transdifferentiation has been implicated in autoimmunity, its precise contribution to disease pathogenesis has remained incompletely understood. Recent advances in single-cell RNA and TCR sequencing provide evidence that, in visceral adipose tissue (VAT), the loss of Treg cells during obesity is driven by the selective transdifferentiation of thymus-derived Treg cells in response to local inflammatory stress. We propose that this process fuels chronic inflammation and may represent one pathway linking Treg instability to chronic VAT inflammation and metabolic dysfunction. Here, we summarize emerging evidence for Treg destabilization in VAT and discuss how local inflammatory and systemic metabolic cues may interact to drive this process, drawing conceptual parallels with autoimmune diseases, particularly type 1 diabetes.

Keywords:  Foxp3; adipose tissue; autoimmunity; metabolism; obesity; pTreg/tTreg; pancreas; β cells

DOI:  https://doi.org/10.3389/fimmu.2025.1698285
NPJ Aging. 2025 Nov 30.

Microglial lipid droplets as therapeutic targets in age-related neurodegenerative diseases.

Soyoung Sung, Hui-Ju Kim, Sun Joo Cha, Minyeop Nahm, Seung Hyun Kim, Min-Soo Kwon.

Monoclonal antibodies approved for Alzheimer's disease (AD), such as lecanemab and aducanumab, have been shown to enhance microglial phagocytic function, underscoring the therapeutic relevance of microglia in neurodegenerative diseases (NDDs). Emerging evidence implicates lipid droplets (LDs) in brain aging and NDDs, particularly through LDs-laden microglia known as lipid droplet-accumulating microglia (LDAM), which exhibit impaired phagocytosis, elevated oxidative stress, and dysregulated lipid metabolism. Among microglial subtypes identified through transcriptomic and functional profiling-including disease-associated microglia (DAM), microglia in neurodegenerative disease (MGnD), white matter-associated microglia (WAM), and dark microglia-LDs-laden microglia have clear metabolic signatures defined by excessive LDs accumulation and disrupted lipid turnover. Here, we discuss the biogenesis of LDs, their pathological accumulation in microglia, and the therapeutic potential of targeting LDs. We further propose a hypothetical mechanism by which LDs clearance restore energy metabolism, nuclear transport, facilitate DNA repair, suppress inflammation, and phagocytosis in microglia. Thus, elucidating LDs dynamics in microglia may provide novel therapeutic avenues for modifying the course of NDDs.

DOI: https://doi.org/10.1038/s41514-025-00295-0
Nat Commun. 2025 Dec 04.

Spatiotemporal profiling of modification-specific proteome secretion uncovers an itaconation-activated tyrosine kinase.

Wenjie Lu, Yanling Zhang, Xinrui Ni, Pian Wang, Shentian Zhuang, Wei Qin.

Macrophages secrete diverse signaling proteins critical for intercellular communication and immune responses, processes tightly regulated by post-translational modifications (PTMs). Itaconate, an immunoregulatory metabolite produced in macrophages, induces widespread intracellular protein modification (itaconation), affecting pathways like the KEAP1-NRF2 axis and glycolysis. However, the impact of itaconation on the extracellular proteome and signaling remains poorly characterized. Herein, we introduce PTM-based secretome profiling (PBSP), a novel approach to identify secreted proteins bearing specific PTMs. The method employs a bioorthogonal probe to label modified proteins in live cells, followed by enrichment of labeled proteins from the culture medium upon secretion. We established a streamlined chemoproteomic workflow integrating spintip-based affinity purification (FISAP) with data-independent acquisition (DIA) mass spectrometry for enhanced sensitivity and coverage. This identified 818 macrophage-secreted itaconated proteins, among which 447 are exosome-dependent. Further biochemical analysis revealed that itaconation of Cys239 on FYN (a tyrosine kinase) enhances its kinase activity in macrophages. We finally demonstrate PBSP's versatility by profiling secreted proteins with other PTMs, including fumarate-induced succination. PBSP provides a powerful platform to explore PTM roles in protein secretion, offering insights into PTMs' regulatory functions in cell-cell communication.

DOI: https://doi.org/10.1038/s41467-025-66508-y
Signal Transduct Target Ther. 2025 Dec 03. 10(1): 394

Adipocytes orchestrate obesity-related chronic inflammation through β2-microglobulin.

Jie Li, Yuhao Li, Xiaoyang Zhou, Shushu Yang, Dong Liu, Hao Wen, Xiaoling Chen, Chengjie Duan, Meiling Yu, Mengjun Zhang, Bo Tang, Yong Wang, Li Wang, Yuzhang Wu.

Chronic inflammation in adipose tissue is widely recognized as a pivotal link connecting obesity to a spectrum of related chronic diseases, including type 2 diabetes, non-alcoholic fatty liver disease, and cardiovascular disorders. In this pathogenic process, the dysregulated interaction between adipocytes and adipose-resident immune cells plays a critical regulatory role; however, the underlying mechanisms governing this abnormal interaction remain largely unknown. In this study, we showed that upregulated β2-microglobulin expression in hypertrophic adipocytes during obesity not only mediated the activation of adipose-resident CD8+ T cells in a cell contact-dependent manner but also facilitated iron overload and the ferroptosis of adipocytes, thereby promoting the M1 polarization of adipose tissue macrophages. Conversely, specific ablation of β2-microglobulin in adipocytes effectively suppressed the activation and accumulation of adipose-resident CD8+ T cells, as well as adipocyte ferroptosis and M1 polarization, ultimately preventing high-fat diet-induced obesity and its related inflammation and metabolic disorders. Additionally, adeno-associated virus-mediated adipose-targeted knockdown of β2-microglobulin has been demonstrated to therapeutically alleviate high-fat diet-induced obesity, as well as its related chronic inflammation and metabolic disorders. Furthermore, our bioinformatic analysis of human adipose transcriptome data revealed a strong correlation between adipose β2-microglobulin and obesity. More importantly, β2-microglobulin is significantly upregulated in adipocytes isolated from patients with obesity. Thus, our findings highlight the pivotal role of adipocytes in obesity-associated chronic inflammation and metabolic disorders via β2-microglobulin-dependent mechanisms.

DOI: https://doi.org/10.1038/s41392-025-02486-3
Redox Biol. 2025 Nov 27. pii: S2213-2317(25)00462-8. [Epub ahead of print]88 103949

β-Hydroxybutyrate ameliorates lipopolysaccharide-induced liver injury through β-hydroxybutyrylation of the SOD2 protein in mice.

Ya-Ping Bai, Yan Zhang, Zhi-Yuan Chen, Kai Li, De-Guo Wang, Shu-Jun Wan, Cui-Wei Zhang, Yue Sun, Zhi-Chao Li, Kun Lv, Lei Zha, Xiang Kong.

  Septic liver injury is a major complication of sepsis, driven in part by oxidative stress-induced macrophage inflammasome activation and hepatocyte apoptosis. β-Hydroxybutyrate (β-OHB), a key ketone body, induces lysine β-hydroxybutyrylation (Kbhb), a novel post-translational modification, yet its role in septic liver injury remains unclear. In this study, we demonstrated that β-OHB markedly increased Kbhb modification of superoxide dismutase 2 (SOD2), a mitochondrial antioxidant enzyme, in both macrophages and hepatocytes. Mechanistically, β-OHB promoted Kbhb at lysine 68 of SOD2, thereby preventing ubiquitin-proteasome-mediated degradation, and then stabilizing the protein, which enhanced its enzymatic activity, and reduced mitochondrial reactive oxygen species accumulation. Consequently, during lipopolysaccharide-induced septic liver injury, SOD2 Kbhb suppressed NLRP3 inflammasome activation in macrophages and protected hepatocytes from apoptosis. Collectively, our findings identify the β-OHB-SOD2-Kbhb axis as a previously unrecognized antioxidant pathway and highlight its therapeutic potential in sepsis.

Keywords:  Apoptosis; Lysine β-hydroxybutyrylation (kbhb); NLRP3 inflammasome; Superoxide dismutase 2 (SOD2); β-Hydroxybutyrate (β-OHB)

DOI:  https://doi.org/10.1016/j.redox.2025.103949
Mol Metab. 2025 Dec 02. pii: S2212-8778(25)00199-1. [Epub ahead of print] 102292

Reprogramming of cholesterol sensing in epithelial cells supports pancreatic inflammation.

Giulia Milan, Olga A Mareninova, Marco Fantuz, Martina Spacci, Carlotta Paoli, Jerik A Pineda, Roberta Noè, Beatrice Calciolari, Roberto Zoncu, Anna S Gukovskaya, Alessandro Carrer.

  Pancreatitis is a common cause of hospitalization that necessitates attentive clinical management. Affected individuals are at risk for pancreatic cancer due to aberrant signaling and empowered cell plasticity. Yet, molecular and cellular dynamics that govern epithelial cell behavior in response to inflammation remain largely elusive. Here we found that inflammation induces Endoplasmic Reticulum-Associated Degradation protein (ERAD)-mediated downregulation of Niemann-Pick type C protein 1 (NPC1), which leads to the sequestration of free cholesterol within acinar cells' lysosomes. Reducing intra-pancreatic cholesterol levels through genetic ablation of Acly ameliorates cerulein-induced pancreatitis, while pharmacological targeting of NPC1 exacerbates tissue damage. Mechanistically, the accumulation of lysosomal cholesterol is sensed by the mechanistic Target of Rapamycin Complex 1 (mTORC1) that promotes metaplasia of pancreatic acinar cells, an event commonly associated to pancreatitis and tissue regeneration. Indeed, cholesterol supplementation or NPC1 inhibition facilitate acinar-to-ductal metaplasia (ADM) both ex vivo and in vivo, in an mTORC1-dependent manner. These results identify a metabolic/signaling axis driving the reprogramming of pancreatic epithelial cells in response to inflammation. This hinges on a nutrient sensing paradigm, previously documented exclusively in pathological conditions.

Keywords:  acinar-to-ductal metaplasia (ADM); cholesterol; lysosome; mTORC1; pancreatitis

DOI:  https://doi.org/10.1016/j.molmet.2025.102292