bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2025–12–14
seventeen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Dietary restriction reprograms CD8+ T cell fate to enhance anti-tumour immunity and immunotherapy responses.
  2. Expression of concern "T cell exhaustion and senescence for ovarian cancer immunotherapy" [Semin. Cancer Biol. 104-105 (2024) 1-15].
  3. The transcription factor Helios restrains the anti-tumor capacity of CD8+ T cells.
  4. T cell immunometabolic dysfunction in a mouse model of cecal ligation and puncture-induced sepsis.
  5. Histone methyltransferase DOT1L maintains cell state and restricts cytotoxic potential of CD8 T cells.
  6. Lypd6b depletion promotes CD8+ T cell-mediated anti-tumor immunity via metabolic reprogramming in colorectal cancer.
  7. A fungal-derived cyclic peptide enhances Th9-mediated antitumor immunity by targeting ZAP70 and SREBP1.
  8. Targeting the pentose phosphate pathway mitigates graft-versus-host disease by rewiring alloreactive T cell metabolism.
  9. Enhanced anti-liver tumor efficacy of chimeric antigen receptor-T cells via SATB1 modulation.
  10. CD2 costimulation strength: A key regulator of T cell function and anti-tumor immunity that is epigenetically regulated.
  11. The changing immune landscape of innate-like T cells and other innate cells throughout life.
  12. Exercise attenuates the hallmarks of aging: Novel perspectives.
  13. Sodium Valproate Drives Propionylation-Mediated Epigenetic Reprogramming to Enhance Mesothelin CAR-T Cell Therapy in Solid Tumors.
  14. Tracing NAD⁺ metabolism uncovers adaptive coordination between host and microbiome during colitis.
  15. Imbalance of stem-like and effector T cell states in children with early type 1 diabetes across conventional and regulatory subsets.
  16. Aging and metabolism in HFpEF: Pathophysiology and therapeutic implications.
  17. Author Correction: Cancer SLC43A2 alters T cell methionine metabolism and histone methylation.
  1. Nat Metab. 2025 Dec 09.
    Dietary restriction reprograms CD8+ T cell fate to enhance anti-tumour immunity and immunotherapy responses.
    Brandon M Oswald, Lisa M DeCamp, Joseph Longo, Michael S Dahabieh, Nicholas Bunda, Benjamin K Johnson, McLane J Watson, Shixin Ma, Samuel E J Preston, Ryan D Sheldon, Michael P Vincent, Abigail E Ellis, Molly T Soper-Hopper, Christine Isaguirre, Dahlya Kamarudin, Hui Shen, Kelsey S Williams, Peter A Crawford, Susan Kaech, H Josh Jang, Evan C Lien, Connie M Krawczyk, Russell G Jones.
      Reducing calorie intake through dietary restriction (DR) slows tumour growth in mammals, yet the underlying mechanisms are poorly defined. Here, we show that DR enhances anti-tumour immunity by optimizing CD8+ T cell function within the tumour microenvironment (TME). Using syngeneic xenograft tumour models, we found that DR induces a profound reprogramming of CD8+ T cell fate in the TME, favouring the expansion of effector T cell subsets with enhanced metabolic capacity and cytotoxic potential, while limiting the accumulation of terminally exhausted T cells. This metabolic reprogramming is driven by enhanced ketone body oxidation, particularly β-hydroxybutyrate (βOHB), which is elevated in both the circulation and tumour tissues of DR-fed mice. βOHB fuels T cell oxidative metabolism under DR, increasing mitochondrial membrane potential and tricarboxylic acid cycle-dependent pathways critical for T cell effector function, including acetyl-CoA production. By contrast, T cells deficient for ketone body oxidation exhibit reduced mitochondrial function, increased exhaustion and fail to control tumour growth under DR conditions. Importantly, DR synergizes with anti-PD1 immunotherapy, further augmenting anti-tumour T cell responses and limiting tumour progression. Our findings reveal that T cell metabolic reprogramming is central to the anti-tumour effects of DR, highlighting nutritional control of CD8+ T cell fate as a key driver of anti-tumour immunity.
    DOI:  https://doi.org/10.1038/s42255-025-01415-6
  2. Semin Cancer Biol. 2025 12;pii: S1044-579X(25)00159-2. [Epub ahead of print]117 130
    Expression of concern "T cell exhaustion and senescence for ovarian cancer immunotherapy" [Semin. Cancer Biol. 104-105 (2024) 1-15].
      
    DOI:  https://doi.org/10.1016/j.semcancer.2025.11.022
  3. Cell Rep. 2025 Dec 11. pii: S2211-1247(25)01452-4. [Epub ahead of print]44(12): 116680
    The transcription factor Helios restrains the anti-tumor capacity of CD8+ T cells.
    Rosa M Rubio, Gerardo Suárez-Rojas, Adrián Albarrán-Godínez, Saraí G De León-Rodríguez, Cristina Aguilar-Flores, Marco Fonseca-Montaño, Michelle Téllez-Sütterlin, Sofia V de Los Santos-Carmona, Karla Guzmán-Barrenechea, Fernando Candanedo-González, Enrique Soto-Perez-de-Celis, Laura Gómez-Romero, Diego Cortez, Marysol González-Yañez, Laura C Bonifaz, Iris K Madera-Salcedo, José C Crispín, Florencia Rosetti.
      Immunotherapy has revolutionized cancer treatment, but it lacks efficacy in a sizable fraction of patients. Therefore, understanding the transcriptional networks that limit CD8+ T cell anti-tumor responses is fundamental. Here, we show that the transcription factor Helios is induced in tumor-infiltrating CD8+ T cells in human and murine cancer. Genetic deletion of Helios in CD8+ T cells reduces tumor growth, decreases the number of intratumoral terminally exhausted CD8+ T cells, and increases the frequency of cells with a transcriptional profile indicative of progenitor capacity. These changes are associated with increased chromatin accessibility in loci encoding stemness-related genes. The combination of Helios and PD-1 deficiencies robustly improves the anti-tumoral capacity of CD8+ T cells. A Helios inhibitor, identified in a small-molecule screen, improves the anti-tumoral effects of PD-1 deficiency. These results demonstrate that Helios represents a therapeutic target that can boost anti-cancer immunotherapy.
    Keywords:  BNTX; CD8(+) T cells; CP: cancer; CP: immunology; Helios; IKZF2; PD-1; T cell exhaustion; TILs; immunotherapy; tumor immunity; tumor-infiltrating T cells
    DOI:  https://doi.org/10.1016/j.celrep.2025.116680
  4. BMC Immunol. 2025 Dec 09.
    T cell immunometabolic dysfunction in a mouse model of cecal ligation and puncture-induced sepsis.
    Xiaoju Liu, Mai Liting, Peiyu Li, Zhong Chen, Zhijian Yu.
       BACKGROUND: T lymphocyte dysfunction is closely associated with immunosuppression in sepsis, whereas the underlying mechanisms are not fully understood.
    RESULTS: In this study, we established a mouse model of cecal ligation and puncture (CLP)-induced sepsis and observed immunometabolic alterations in splenic T cells. Serum energy metabolites related to glycolysis and the tricarboxylic acid (TCA) cycle were imbalanced. Splenic T cells from septic mice showed a shift in subset distribution, with decreased naïve T cells and increased effector populations, along with concurrent activation and exhaustion phenotypes. Notably, mitochondrial mass and mitochondrial membrane potential were significantly diminished in both CD4+ and CD8+ T cell, correlated with increased programmed cell death protein 1 (PD-1) expression. Transmission electron microscopy further confirmed mitochondrial morphological alterations in CLP-derived CD3+ T cells. Furthermore, seahorse assays demonstrated impaired metabolic reprogramming capacity in activated CLP splenic CD3+ T cells, with suppressed glycolytic and oxidative phosphorylation responses. This impairment was coupled with reduced fold-increases in mitochondrial mass and mitochondrial membrane potential levels upon activation in both CD4+ and CD8+ T cell compared to controls. Clinically, peripheral T cells from septic patients showed elevated CD69 and PD-1 expression, a significant increase in CD39 and a decrease in CD73, increased mitochondrial mass and decreased mitochondrial membrane potential, particularly in those with septic shock.
    CONCLUSIONS: Our findings provide several layers of T cell dysfunction in sepsis, linking subset redistribution, an exhausted phenotype, mitochondrial impairment, and reduced proliferative capacity, suggesting that future therapeutic interventions aiming to reverse sepsis-induced immunosuppression may require a combinatorial approach.
    Keywords:  Immune metabolism; Mitochondrial mass; Mitochondrial membrane potential; Sepsis; T cell
    DOI:  https://doi.org/10.1186/s12865-025-00790-9
  5. Sci Adv. 2025 Dec 12. 11(50): eadw1289
    Histone methyltransferase DOT1L maintains cell state and restricts cytotoxic potential of CD8 T cells.
    Muddassir Malik, Willem-Jan de Leeuw, Muhammad Assad Aslam, Eliza Mari Kwesi-Maliepaard, Teun van den Brand, Bram van den Broek, Maxime Kempers, Liesbeth Hoekman, Natalie Proost, Tibor van Welsem, Nikolina Bąbała, Elselien Frijlink, Elzo de Wit, Jannie Borst, Heinz Jacobs, Fred van Leeuwen.
      The histone methyltransferase DOT1L is emerging as a central epigenetic regulator in immune cells. Loss of DOT1L during development of CD8 T cells in vivo leads to gain of memory characteristics but has also been reported to compromise CD8 T cell viability and antitumor reactivity. Here, we determined the cell-intrinsic role of DOT1L in mature mouse CD8 T cells. After conditional deletion of Dot1L in vitro, CD8 T cells retained in vivo proliferative capacity and antitumor reactivity. Moreover, Dot1L knockout CD8 T cells showed increased antigen-specific cytotoxicity toward tumor cells in vitro. Mechanistically, loss of DOT1L resulted in an altered cell state with loss of T cell and gain of innate-like features. These transcriptional changes were mediated by loss of DOT1L methyltransferase activity in a dose-dependent manner. Our findings show that in mature CD8 T cells, ablation of DOT1L activity is well tolerated and reprograms them to gain innate-like memory cell characteristics and enhance intrinsic cytotoxic capacity.
    DOI:  https://doi.org/10.1126/sciadv.adw1289
  6. Nat Commun. 2025 Dec 11.
    Lypd6b depletion promotes CD8+ T cell-mediated anti-tumor immunity via metabolic reprogramming in colorectal cancer.
    Ting Liu, Fanxin Zeng, Zuyin Li, Leirong Cheng, Xuanxuan Yan, Haiqiang Chen, Qin Liu, Xue Li, Zhao Li, Jiaheng Yao, Dan Xu, Zhinan Chen, Fengchao Wang, Jun Wang, Jinhua Zhang.
      Lymphocyte antigen-plasminogen activator urokinase receptor domain-containing protein 6B (Lypd6b) is a newly identified molecule associated with neuromodulation. However, the role of Lypd6b in regulating the tumor microenvironment and its impact on CD8+ T cell-mediated antitumor immunity remain unknown. Here, we observe that Lypd6b expression is increased significantly in colorectal cancer (CRC) tumor tissues compared to normal tissues. Lypd6b is mainly expressed in CD8+ T cells in tumor tissues. Lypd6b knockout (Lypd6b-/-) mice are resistant to AOM/DSS-induced tumorigenesis. Furthermore, global deficiency or CD8+ cell deficiency of Lypd6b inhibits MC38 or CMT-93 tumor growth and promotes the infiltration of CD8+ T cells. Mechanistically, Lypd6b deficiency promotes activation and function of CD8+ T cells in anti-tumor response with increased glycolysis and reduced oxidative phosphorylation in a PI3K/mTOR/LDHA pathway-dependent manner. Notably, Lypd6b deficient CD8+ T cells have a more potent antitumor effect when combined with anti-PD1 antibody. Thus, Lypd6b as a negative regulator for T cell immunity promotes CRC development, providing a molecular target with therapeutic potential in CRC.
    DOI:  https://doi.org/10.1038/s41467-025-67344-w
  7. J Clin Invest. 2025 Dec 09. pii: e196907. [Epub ahead of print]
    A fungal-derived cyclic peptide enhances Th9-mediated antitumor immunity by targeting ZAP70 and SREBP1.
    Wenli Zhao, Yang Zhou, Yuyang Chen, Yicheng Sun, Jiaxin Tang, Yihan Zhu, Jie Ren, Tianxu Du, Handuo Wang, Yuan Gao, Yu Hu, Ling Jiang, Tomohiko Ohwada, Qi Luo, Enguang Bi.
      Adoptive cell therapy (ACT) relies on durable and functional T cells to mediate tumor clearance. Th9 cells are a metabolically fit CD4+ T cell subset with strong persistence but limited cytotoxicity. Here, we identified endomelipeptide A (EpA), a cyclic peptide isolated from Ganoderma lucidum-associated endophytic fungi, as a potent enhancer of Th9 differentiation. EpA promoted a cytotoxic Th9 phenotype with enhanced mitochondrial function and metabolic fitness. Mechanistically, EpA dually targeted ZAP70 and SREBP1, coupling T cell receptor (TCR) signaling activation with lipid metabolism suppression. EpA-treated Th9 cells mediated robust, CD8+ T cell-dependent tumor control and enhanced the efficacy of human Th9 CAR-T therapy in vivo. These findings establish EpA as a distinct cyclic peptide that reprograms Th9 cells and provides a potential approach to boost ACT efficacy.
    Keywords:  Cancer immunotherapy; Immunology; Oncology; Peptides; T cells
    DOI:  https://doi.org/10.1172/JCI196907
  8. JCI Insight. 2025 Dec 08. pii: e192774. [Epub ahead of print]10(23):
    Targeting the pentose phosphate pathway mitigates graft-versus-host disease by rewiring alloreactive T cell metabolism.
    Saeed Daneshmandi, Eun Ko, Qi Yan, Jee Eun Choi, Prashant K Singh, Richard M Higashi, Andrew N Lane, Teresa Wm Fan, Jingxin Qiu, Sophia Hani, Keli L Hippen, Jianmin Wang, Philip L McCarthy, Bruce R Blazar, Hemn Mohammadpour.
      Glycolysis fuels cytotoxic allogeneic T cells in acute graft-versus-host disease (aGvHD), but the downstream role of glucose metabolism in modulating aGvHD remains unclear. Targeting glycolysis or glucose receptors is toxic. Therefore, we explored alternative glucose-dependent pathways, focusing on the pentose phosphate pathway (PPP). Single-cell RNA sequencing revealed PPP upregulation in allogeneic T cells during allogeneic hematopoietic cell transplantation (allo-HCT). We showed that donor T cell deficiency in 6-phosphogluconate dehydrogenase (6PGD), the second rate-limiting enzyme in the PPP, significantly reduced aGvHD severity and mortality in murine models. Functional assays demonstrated that PPP blockade led to proliferation arrest without inducing apoptosis. PPP blockade shifted T cell metabolism away from T cell dependency on glycolysis for rapid T cell proliferation. Pharmacological inhibition of the PPP through 6PGD blockade with 6-aminonicotinamide (6AN) effectively reduced aGvHD severity, like donor 6PGD-deficient T cells in an allogeneic aGvHD model. Similarly, 6AN reduced xenogeneic GvHD lethality. 6PGD inhibition preserved the graft-versus-tumor (GvT) effect, with the generation of a small subset of granzyme Bhi effector T cells with potent antitumor activity. These findings highlight the PPP as a key regulator of allogeneic T cell proliferation and differentiation and identify 6PGD as a promising therapeutic target to mitigate aGvHD severity while preserving beneficial GvT effects.
    Keywords:  Immunology; Oncology; Stem cell transplantation; T cells
    DOI:  https://doi.org/10.1172/jci.insight.192774
  9. Cell Death Dis. 2025 Dec 10.
    Enhanced anti-liver tumor efficacy of chimeric antigen receptor-T cells via SATB1 modulation.
    Lin Zhang, Chenxi Cheng, Xinyi Bi, Jiani Cao, Xiaoyan Li, Tongbiao Zhao.
      Although Chimeric antigen receptor (CAR) T-cell therapy has achieved remarkable success in treating hematopoietic malignancies, its clinical application in solid tumors is profoundly hindered by persistent T-cell exhaustion within the immunosuppressive tumor microenvironment (TME). Here, we identified SATB1-a genome organizer regulating chromatin architecture-as a key suppressor of CAR-T cell exhaustion. In Glypican-3 (GPC3)-targeted CAR-T cells, SATB1 was significantly downregulated in tumor-infiltrating exhausted populations. SATB1 overexpression not only reduced expression of multiple inhibitory receptors (PD-1, CTLA-4, TIM3, and LAG-3) but also promoted a central memory phenotype, enhancing cytokine production and cytotoxicity against hepatocellular carcinoma (HCC) cells in vitro. In vivo, SATB1-engineered CAR-T cells exhibited superior tumor control and promoted survival, accompanied by reduced exhaustion markers in tumor-infiltrating T cells. These functional improvements are consistent with the reported role of SATB1 in modulating T cell exhaustion, positioning it as a multifunctional enhancer of CAR-T cell fitness. Collectively, our study unveils SATB1 as a multifunctional modulator that simultaneously targets exhaustion and memory differentiation, offering a novel strategy to enhance CAR-T efficacy against solid tumors.
    DOI:  https://doi.org/10.1038/s41419-025-08307-3
  10. iScience. 2025 Dec 19. 28(12): 113977
    CD2 costimulation strength: A key regulator of T cell function and anti-tumor immunity that is epigenetically regulated.
    Philippos Demetriou, Maria Iakovou, Gregoria Gregoriou, Dimitris Vrachnos, Jianxiang Chi, Vasilia Tamamouna, Georgia Stavrou, Stavros Constantinou, Vakis Papanastasiou, Athos Antoniades, Paul Costeas.
      CD2 is a key costimulatory receptor on human T cells, but its surface abundance regulation and its functional significance remain incompletely defined. We found that CD2 expression is markedly reduced in CD4+ and CD8+ tumor-infiltrating T cells from human brain tumors. To identify factors sustaining CD2 expression, we performed a genome-wide CRISPR-Cas9 screen in Jurkat T cells and discovered BAP1 and SUZ12 as regulators. Loss of BAP1 caused downregulation of CD2, TRAC, and other costimulatory receptors, with CD2 and TRAC expression remaining impaired even after activation. Transcriptomic analysis linked BAP1 deficiency to the disruption of programs controlling T cell identity and differentiation, while histone deacetylase inhibition partially restored CD2. In primary human T cells, reduced CD2 costimulation impaired the magnitude of proliferation and IFN-γ production. These findings identify BAP1 as a central regulator of receptor expression and highlight CD2 as a tunable modulator of human T cell responses.
    Keywords:  immunology; microenvironment
    DOI:  https://doi.org/10.1016/j.isci.2025.113977
  11. Immunol Cell Biol. 2025 Dec 10.
    The changing immune landscape of innate-like T cells and other innate cells throughout life.
    Marziyeh Taheri, Christopher Menne, Jeremy Anderson, Louis Perriman, Shuo Li, Stuart P Berzins, Paul V Licciardi, Thomas M Ashhurst, Sedigheh Jalali, Daniel G Pellicci.
      Spectral flow cytometry is an advanced immunological tool that can enable comprehensive analysis of the immune system by simultaneously comparing innate and adaptive immune cells. Here, using a 40-color antibody panel, we advance our knowledge of innate-like cells by investigating chemokine receptors and maturation markers not usually assessed on these populations, examining age-related effects on these immune cell subsets. We characterize phenotypic changes of peripheral blood mononuclear cells (PBMCs) in three age groups: newborns (cord blood), adults aged 20-30 years, and adults aged > 70 years. We compare the age-related changes of innate cells, including ILCs, NK cells, monocytes, dendritic cells, and innate-like T cells, comparing them with memory T cells. We also examine subsets of CD4-CD8- double-negative (DN) T cells and CD3+CD161+ T cells, revealing they are phenotypically similar to known subsets of innate-like T cells, and they also increase in frequency in an age-related manner. The frequencies of ILC1 increased with age, ILC2 remained stable, whereas ILC3 peaked in young adults, and were higher than cord and older adults. Notably, we identify the NK cell maturation marker, CD57, as a universal marker that defines aging populations of both innate and adaptive immune cells. This study enhances our understanding of the ontogeny of human immune cells, highlighting significant age-related changes in the frequency and phenotype of innate-like populations of immune cells.
    Keywords:  CD markers; aging; immunophenotyping; innate cells; innate‐like T cells; spectral flow cytometry
    DOI:  https://doi.org/10.1111/imcb.70070
  12. J Sport Health Sci. 2025 Dec 04. pii: S2095-2546(25)00116-4. [Epub ahead of print] 101108
    Exercise attenuates the hallmarks of aging: Novel perspectives.
    Yan Qiu, Benjamin Fernández-García, H Immo Lehmann, Guoping Li, Guido Kroemer, Carlos López-Otín, Junjie Xiao.
      The number and proportion of individuals aged 60 years and older are steadily increasing. However, increased life expectancy is accompanied by a decline in functional capacity and a heightened risk of age-related diseases, ultimately leading to reduced quality of life. Interventions that support physiological function in later life and hence extend healthspan are therefore of considerable importance. Among these, regular physical exercise is strongly associated with numerous health benefits and is recognized as a key strategy for promoting healthy aging and extending healthspan. In this review, we highlight the impact of an active lifestyle, particularly regular physical activity, on the major hallmarks of aging. These include genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, impaired macroautophagy, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, changes in the extracellular matrix, stem cell exhaustion, altered intercellular communication, chronic inflammation, dysbiosis, and psychosocial isolation. A deeper understanding of the mechanisms by which exercise confers these benefits will aid in enhancing both physical and mental health in the elderly and in mitigating the onset of aging-associated diseases.
    Keywords:  Exercise; Hallmarks of aging; Healthspan; Healthy aging
    DOI:  https://doi.org/10.1016/j.jshs.2025.101108
  13. Mol Ther. 2025 Dec 11. pii: S1525-0016(25)01044-5. [Epub ahead of print]
    Sodium Valproate Drives Propionylation-Mediated Epigenetic Reprogramming to Enhance Mesothelin CAR-T Cell Therapy in Solid Tumors.
    Jiannan Chen, Wenying Li, Shuai Wang, Jiayi Li, Lianfeng Zhao, Xudong Ao, Wenyu Wang, Li Zhu, Haipeng Rao, Shichu Xu, Mengru Wen, Zhigang Hu, Feiyan Pan, Lingfeng He, Lili Gu, Weijia Fang, Shengjing Xu, Junqing Liang, Peng Zhao, Haoyan Chen, Zhigang Guo.
      Chimeric antigen receptor (CAR)-T cell therapy has shown success in hematologic malignancies but remains limited in solid tumors due to poor persistence, migration, and TME-induced exhaustion. In an investigator-initiated trial in relapsed/refractory ovarian cancer, mesothelin-targeted CAR-T cells demonstrated a 75% partial response rate and good safety. To enhance efficacy, we combined CAR-T therapy with sodium valproate (VPA), a clinically approved histone deacetylase inhibitor (HDACi). VPA-treated CAR-T cells (CAR-T+VPA) showed improved cytotoxicity, reduced exhaustion, and enhanced tumor infiltration. Mechanistically, VPA induced histone propionylation, particularly H3K56pr, leading to transcriptional activation of key genes. LOX promoted migration and adhesion, while GUCY1B3 enhanced metabolic fitness. CUT&Tag and RNA-seq analyses confirmed VPA-driven epigenetic remodeling of pathways linked to T cell persistence and effector function. CAR-T+VPA cells exhibited elevated oxidative phosphorylation and glycolysis, supporting sustained activity in hostile tumor environments. In xenograft models of ovarian and triple-negative breast cancer, VPA significantly improved tumor control and survival without added toxicity. These findings support metabolic-epigenetic modulation as a strategy to improve CAR-T therapy in solid tumors.
    DOI:  https://doi.org/10.1016/j.ymthe.2025.12.021
  14. Res Sq. 2025 Dec 04. pii: rs.3.rs-8195970. [Epub ahead of print]
    Tracing NAD⁺ metabolism uncovers adaptive coordination between host and microbiome during colitis.
    Melanie McReynolds, Abrar Alsaadi, Lina Welz, Anant Pothakamury, Clara Gilloteau, Praveena Prasad, Mahmoud Yahia, Jaedon Sadler, Jaclyn Smith, Brenita Jenkins, Garret Diven, Johanna Bornhäuser, Taous Mekdoud, Shuchang Tian, Philip Rosenstiel, Stefan Schreiber, Jordan Bisanz, Konrad Aden.
      Host-microbiota metabolic interactions critically regulate nicotinamide adenine dinucleotide (NAD+) homeostasis, and their disruption is increasingly linked to chronic diseases including inflammatory bowel disease (IBD). However, it remains unclear whether NAD+ dysregulation in IBD arises from impaired production, enhanced consumption, or both. Using multi-omics approaches and stable isotope-labeled NAD+ precursors administered via intravenous infusion in a murine model of dextran sulfate sodium (DSS)-induced colitis, we mapped tissue- and lumen-specific NAD+ metabolism under inflammatory stress. Our results reveal tissue-specific rewiring of NAD+ metabolism, with increased flux through the salvage pathway compensating for reduced de novo NAD+ synthesis from tryptophan. In parallel, microbial de novo NAD+ production was elevated, highlighting a cooperative host-microbiota response to inflammatory stress. These findings demonstrate differential regulation of NAD+ biosynthesis during acute colitis and underscore the dynamic interplay between host and microbial metabolism in maintaining NAD+ homeostasis under inflammatory conditions.
    DOI:  https://doi.org/10.21203/rs.3.rs-8195970/v1
  15. Nat Commun. 2025 Dec 11.
    Imbalance of stem-like and effector T cell states in children with early type 1 diabetes across conventional and regulatory subsets.
    Veronika Niederlova, Ales Neuwirth, Vit Neuman, Juraj Michalik, Bela Charvatova, Martin Modrak, Zdenek Sumnik, Ondrej Stepanek.
      Type 1 diabetes (T1D) is an autoimmune disease caused by the loss of self-tolerance toward insulin-producing pancreatic β-cells. Its etiology remains incompletely understood but involves dysregulated T cell responses. Here, we perform single-cell transcriptomic analysis of peripheral blood T cells from children newly diagnosed with T1D, the same children after one year, and healthy donors. We observe that children with diabetes show diminished effector and cytotoxic programs and enhanced stemness-associated gene signature across diverse T cell subsets, especially at diagnosis. In parallel, we detect signs of impaired regulatory capacity in regulatory T cells and regulatory TR3-56 cells. These findings are supported by flow cytometry analysis of the same cohort and reanalysis of publicly available datasets. Overall, our results suggest that T1D is associated with impaired T cell effector differentiation and regulatory T cell dysfunction, both of which may contribute to immune imbalance and loss of self-tolerance.
    DOI:  https://doi.org/10.1038/s41467-025-66459-4
  16. Metabolism. 2025 Dec 04. pii: S0026-0495(25)00329-4. [Epub ahead of print] 156460
    Aging and metabolism in HFpEF: Pathophysiology and therapeutic implications.
    Min Ye, Shenghui Feng, Zixuan Xu, Wenfeng He, Chen Liu, Wengen Zhu.
      Heart failure with preserved ejection fraction (HFpEF) is increasingly recognized as an age-predominant syndrome characterized by diastolic dysfunction despite preserved systolic performance. In the aged myocardium, fatty acid oxidation capacity declines, while glycolytic flux increases; however, impaired pyruvate oxidation limits mitochondrial glucose oxidation, resulting in suboptimal ATP yield per oxygen molecule and worsening energetic inefficiency. Mitochondrial deficits, marked by reduced biogenesis, NAD+ depletion related to reduced sirtuin activity and consequent hyperacetylation of oxidative enzymes, and impaired electron-transport capacity, further diminish bioenergetic reserve and elevate reactive oxygen species generation. Concurrently, inflammaging and proteostatic collapse promote chronic low-grade inflammation, misfolded protein accumulation, and myocardial fibrosis, collectively contributing to increased ventricular stiffness and progressive HFpEF development. Therapeutic strategies targeting these interconnected pathways show considerable promise. Preclinical studies suggest that interventions such as NAD+ precursor supplementation, mTORC1 inhibition, and β-hydroxybutyrate administration can ameliorate HFpEF-like phenotypes by improving mitochondrial efficiency and reducing inflammation. SGLT2 inhibitors and GLP-1 receptor agonists confer clinically proven benefits in HFpEF, likely via systemic metabolic reprogramming toward more oxygen-efficient substrates and attenuation of inflammation. This review underscores the critical role of aging-associated metabolic and mitochondrial derangements in HFpEF pathogenesis and highlights mechanistically tailored interventions as the next frontier in managing this challenging, age-related syndrome.
    Keywords:  Cardiac aging; Heart failure with preserved ejection fraction; Metabolic remodeling; Mitochondrial dysfunction; Therapeutic targets
    DOI:  https://doi.org/10.1016/j.metabol.2025.156460
  17. Nature. 2025 Dec 12.
    Author Correction: Cancer SLC43A2 alters T cell methionine metabolism and histone methylation.
    Yingjie Bian, Wei Li, Daniel M Kremer, Peter Sajjakulnukit, Shasha Li, Joel Crespo, Zeribe C Nwosu, Li Zhang, Arkadiusz Czerwonka, Anna Pawłowska, Houjun Xia, Jing Li, Peng Liao, Jiali Yu, Linda Vatan, Wojciech Szeliga, Shuang Wei, Sara Grove, J Rebecca Liu, Karen McLean, Marcin Cieslik, Arul M Chinnaiyan, Witold Zgodziński, Grzegorz Wallner, Iwona Wertel, Karolina Okła, Ilona Kryczek, Costas A Lyssiotis, Weiping Zou.
      
    DOI:  https://doi.org/10.1038/s41586-025-09845-8
This page is being maintained by Thomas Krichel. It was last updated on 2025‒12‒14 at 6:57.