Non-oxidative pentose phosphate pathway controls regulatory T cell function by integrating metabolism and epigenetics

Liu, Qi; Zhu, Fangming; Liu, Xinnan; Lu, Ying; Yao, Ke; Tian, Na; Tong, Lingfeng; Figge, David A.; Wang, Xiuwen; Han, Yichao; Li, Yakui; Zhu, Yemin; Hu, Lei; Ji, Yingning; Xu, Nannan; Li, Dan; Gu, Xiaochuan; Liang, Rui; Gan, Guifang; Wu, Lifang; Zhang, Ping; Xu, Tian‐Le; Hu, Hui; Hu, Zeping; Xu, Hao; Ye, Dan; Yang, Hui; Li, Bin; Tong, Xuemei

doi:10.1038/s42255-022-00575-z

Cited by 41 publications

(40 citation statements)

References 60 publications

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“…In particular, elegant studies combining metabolic therapy and epigenetic therapy in hematological malignancies provide a milestone in targeting the epigenetic-metabolic circuit, hopefully becoming a novel paradigm for cancer treatment. Although the prospect is exciting, most of our related knowledge is limited to in vitro studies and is usually context-specific, without considering the effects on immune cells [335][336][337]. More confirmatory evidence should be explored before actual clinical practice.…”

Section: Discussionmentioning

confidence: 99%

Crosstalk between metabolic reprogramming and epigenetics in cancer: updates on mechanisms and therapeutic opportunities

Jia

et al. 2022

Cancer Communications

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Reversible, spatial, and temporal regulation of metabolic reprogramming and epigenetic homeostasis are prominent hallmarks of carcinogenesis. Cancer cells reprogram their metabolism to meet the high bioenergetic and biosynthetic demands for vigorous proliferation. Epigenetic dysregulation is a common feature of human cancers, which contributes to tumorigenesis and maintenance of the malignant phenotypes by regulating gene expression. The epigenome is sensitive to metabolic changes. Metabolism produces various metabolites that are substrates, cofactors, or inhibitors of epigenetic enzymes. Alterations in metabolic pathways and fluctuations in intermediate metabolites convey information regarding the intracellular metabolic status into the nucleus by modulating the activity of epigenetic enzymes and thus remodeling the epigenetic landscape, inducing transcriptional responses to heterogeneous metabolic requirements. Cancer metabolism is regulated by epigenetic machinery at both transcriptional and post‐transcriptional levels. Epigenetic modifiers, chromatin remodelers and non‐coding RNAs are integral contributors to the regulatory networks involved in cancer metabolism, facilitating malignant transformation. However, the significance of the close connection between metabolism and epigenetics in the context of cancer has not been fully deciphered. Thus, it will be constructive to summarize and update the emerging new evidence supporting this bidirectional crosstalk and deeply assess how the crosstalk between metabolic reprogramming and epigenetic abnormalities could be exploited to optimize treatment paradigms and establish new therapeutic options. In this review, we summarize the central mechanisms by which epigenetics and metabolism reciprocally modulate each other in cancer and elaborate upon and update the major contributions of the interplays between epigenetic aberrations and metabolic rewiring to cancer initiation and development. Finally, we highlight the potential therapeutic opportunities for hematological malignancies and solid tumors by targeting this epigenetic‐metabolic circuit. In summary, we endeavored to depict the current understanding of the coordination between these fundamental abnormalities more comprehensively and provide new perspectives for utilizing metabolic and epigenetic targets for cancer treatment.

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Section: Discussionmentioning

confidence: 99%

Crosstalk between metabolic reprogramming and epigenetics in cancer: updates on mechanisms and therapeutic opportunities

Jia

et al. 2022

Cancer Communications

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“…A study reported that glycogen metabolism regulates inflammatory responses in patients with sepsis ( 64 ). Additionally, PPP was a key pathway for regulating Treg cells ( 65 ). Daneshmandi et al ( 66 ) reported that blocking 6-phosphogluconate dehydrogenase in the oxidative PPP resulted in a substantial reduction of Tregs' suppressive function and shifts toward Th1, Th2, and Th17 phenotypes, which led to the development of the fetal inflammatory disorder in a mouse model.…”

Section: Discussionmentioning

confidence: 99%

Study on the protective effect of berberine treatment on sepsis based on gut microbiota and metabolomic analysis

et al. 2022

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IntroductionSepsis, an infection with multiorgan dysfunction, is a serious burden on human health. Berberine (BBR), a bioactive component, has a protective effect on sepsis and the effect may be related to gut microbiota. However, studies on the role of BBR with gut microbiota in sepsis are lacking. Therefore, this study investigated the ameliorative effects and the underlying mechanisms of BBR on cecal ligature and puncture (CLP) rats.MethodsThis study has observed the effect of BBR on pathological injury, Inflammation, intestinal barrier function, gut microbiota, and metabolite change in CLP rats by Hematoxylin-eosin staining, enzyme-linked immunosorbent assays, flow cytometry, 16S rDNA, and metabolomics analyses.ResultsThe inhibition effects of BBR treatment on the histological damage of the lung, kidney, and ileum, the interleukin (IL)-1b, IL-6, IL-17A, and monocyte chemokine-1 levels in serum in CLP rats were proved. Also, the BBR inhibited the diamine-oxidase and fluorescein isothiocyanate-dextran 40 levels, suggesting it can improve intestinal barrier function disorders. The cluster of differentiation (CD) 4+, CD8+, and CD25+ Forkhead box protein P3 (Foxp3) + T lymphocytes in splenocytes were up-regulated by BBR, while the IL-17A+CD4+ cell level was decreased. The abundance of gut microbiota in CLP rats was significantly different from that of the sham and BBR treatment rats. The significantly changed metabolites in the serum mainly included carbohydrates, phenols, benzoic acids, alcohols, vitamins et al. Additionally, this study predicted that the biological mechanism of BBR to ameliorate sepsis involves glycolysis-, nucleotide-, and amino acid-related metabolic pathways.DiscussionThis study proved the strong correlation between the improvement effect of BBR on sepsis and gut microbiota and analyzed by metabolomics that gut microbiota may improve CLP rats through metabolites, providing a scientific basis for BBR to improve sepsis and a new direction for the study of the biological mechanism.

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“…Blood-derived Tregs from patients with autoimmune diseases, including MS, rheumatoid arthritis (RA), and systemic lupus erythematosus, exhibit impaired mitochondrial metabolism and function, resulting in oxidative stress and cell death [83,99]. Similarly, function of the PPP, which is involved in redox homeostasis and biosynthesis, and uptake of cysteine, which is necessary for regulation of oxidative stress, may also be impaired in Tregs from patients with autoimmune diseases [30,55]. The mechanisms by which these perturbations occur during autoimmunity are not well defined.…”

Section: Modulation Of Treg Function In Vivomentioning

confidence: 99%

Targeting regulatory T cell metabolism in disease: Novel therapeutic opportunities

2023

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Regulatory T cells (Tregs) are essential for immune homeostasis and suppression of pathological autoimmunity but can also play a detrimental role in cancer progression via inhibition of anti‐tumor immunity. Thus, there is broad applicability for therapeutic Treg targeting, either to enhance function, for example, through adoptive cell therapy (ACT), or to inhibit function with small molecules or antibody‐mediated blockade. For both of these strategies, the metabolic state of Tregs is an important consideration since cellular metabolism is intricately linked to function. Mounting evidence has shown that targeting metabolic pathways can selectively promote or inhibit Treg function. This review aims to synthesize the current understanding of Treg metabolism and discuss emerging metabolic targeting strategies in the contexts of transplantation, autoimmunity, and cancer. We discuss approaches to gene editing and cell culture to manipulate Treg metabolism during ex vivo expansion for ACT, as well as in vivo nutritional and pharmacological interventions to modulate Treg metabolism in disease states. Overall, the intricate connection between metabolism and phenotype presents a powerful opportunity to therapeutically tune Treg function.

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Non-oxidative pentose phosphate pathway controls regulatory T cell function by integrating metabolism and epigenetics

Cited by 41 publications

References 60 publications

Crosstalk between metabolic reprogramming and epigenetics in cancer: updates on mechanisms and therapeutic opportunities

Crosstalk between metabolic reprogramming and epigenetics in cancer: updates on mechanisms and therapeutic opportunities

Study on the protective effect of berberine treatment on sepsis based on gut microbiota and metabolomic analysis

Targeting regulatory T cell metabolism in disease: Novel therapeutic opportunities

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