bims-imicid 2025-04-27 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2025–04–27
twenty-six papers selected by
Dylan Ryan, University of Cambridge

SENP1-Sirt3 axis promotes cholesterol biosynthesis in tumor-associated macrophages to suppress anti-tumor immunity.
A host-pathogen metabolic synchrony that facilitates disease tolerance.
SVF mediates immunometabolic alterations in burn-induced hypermetabolic adipose tissue via mitochondrial transfer.
A new method to measure cell metabolism of rare cells in vivo reveals a high oxidative phosphorylation dependence of lung T cells.
Exogenous L-Serine Alleviates Pasteurella multocida-Induced Inflammation by Reprogramming the Transcription and Metabolism of Macrophages.
NEDDylation regulates CD8+ T cell metabolism and anti-tumor immunity.
Mitochondrial transfer drives immune evasion in tumor microenvironment.
Obesity-Induced Metabolic Priming Exacerbates SARS-CoV-2 Inflammation.
Autofluorescence lifetime imaging classifies human B and NK cell activation state.
Glucose deprivation and identification of TXNIP as an immunometabolic modulator of T cell activation in cancer.
Glucose- and glutamine-driven de novo nucleotide synthesis facilitates WSSV replication in shrimp.
The metabolic dialogue between intratumoural microbes and cancer: implications for immunotherapy.
Loss of neurofibromin induces inflammatory macrophage phenotypic switch and retinal neovascularization via GLUT1 activation.
Metabolic Homeostasis of Immune Cells Modulates Cardiovascular Diseases.
MAVS is a sensor of fumarate during antiviral immunity.
Protein Synthesis and Metabolism in T Cells.
Phosphatidylethanolamine species with n-3 and n-6 fatty acids modulate macrophage lipidome and attenuate responses to LPS stimulation.
LDHA-lactate axis modulates mitophagy inhibiting CSFV replication.
Human γδ T Cell Function Is Impaired Upon Mevalonate Pathway Inhibition.
Mitochondrial protein OPA1 is required for the expansion of effector CD8 T cells.
Targeting CD38 immunometabolic checkpoint improves metabolic fitness and cognition in a mouse model of Alzheimer's disease.
Ureaplasma urealyticum GrpE protein elicits glycolysis-mediated inflammatory responses through TLR2 in macrophages.
DHODH modulates immune evasion of cancer cells via CDP-Choline dependent regulation of phospholipid metabolism and ferroptosis.
Cholesterol pathway gene variants and reduced keratinocyte cholesterol support a final common druggable pathway in hyperproliferative inflammatory skin diseases.
Cholesterol 25-hydroxylase inhibits Newcastle disease virus replication by enzyme activity-dependent and direct interaction with nucleocapsid protein.
Maternal B12 deficiency during pregnancy dysregulates fatty acid metabolism and induces inflammation in human adipose tissue.

Cancer Lett. 2025 Apr 17. pii: S0304-3835(25)00294-0. [Epub ahead of print] 217728

SENP1-Sirt3 axis promotes cholesterol biosynthesis in tumor-associated macrophages to suppress anti-tumor immunity.

Guoyuan Peng, Xinyu Yang, Jianli He, Mingming Zhang, Kexin Liu, Jun Tu, Hongsheng Tan, Innocent Agida, Wei Zhou, Jinke Cheng, Tianshi Wang.

  Tumor-associated macrophages (TAMs) play a multifaceted role in the tumor microenvironment, notably by suppressing antitumor immune responses through immunosuppressive mechanisms. TAMs secrete a range of cytokines that simultaneously inhibit T cell function and foster a microenvironment that supports tumor progression and dissemination. Our study has delved into the intricate relationship between the metabolic reprogramming of TAMs and their impact on tumor progression. Mitochondrial metabolic reprogramming mediated by the SENP1-Sirt3 axis altered the dynamics and activity of tumor-infiltrating immune cells, including macrophages and CD8+ T lymphocytes. SENP1-Sirt3 axis increases the level of acetyl-CoA in macrophage mitochondria, which in turn promotes cholesterol biosynthesis in macrophages. The upregulation of cholesterol synthesis is a key factor in driving macrophage polarization towards the immunosuppressive M2 phenotype, which in turn supports tumor development. Notably, increased cholesterol levels contributed to a reduction in the number and activity of CD8+ T cells, which are essential for mounting an effective immune response against cancer cells. These findings suggest that targeting cholesterol biosynthesis in TAMs may be a promising strategy for cancer immunotherapy. SIGNIFICANCE: Activation of the SENP1-Sirt3 axis initiates mitochondrial metabolic reprogramming in tumor-associated macrophages (TAMs), leading to enhanced cholesterol and acetyl-CoA production, M2 macrophage polarization, and impaired CD8+ T cell anti-tumor responses.

Keywords:  SENP1-Sirt3 axis; acetyl-CoA; cholesterol biosynthesis; tumor-associated macrophages

DOI:  https://doi.org/10.1016/j.canlet.2025.217728
Nat Commun. 2025 Apr 19. 16(1): 3729

A host-pathogen metabolic synchrony that facilitates disease tolerance.

Ying-Tsun Chen, Gaurav Kumar Lohia, Samantha Chen, Zihua Liu, Tania Wong Fok Lung, Chu Wang, Sebastián A Riquelme.

Disease tolerance mitigates organ damage from non-resolving inflammation during persistent infections, yet its underlying mechanisms remain unclear. Here we show, in a Pseudomonas aeruginosa pneumonia mouse model, that disease tolerance depends on the mitochondrial metabolite itaconate, which mediates cooperative host-pathogen interactions. In P. aeruginosa, itaconate modifies key cysteine residues in TCA cycle enzymes critical for succinate metabolism, inducing bioenergetic stress and promoting the formation biofilms that are less immunostimulatory and allow the bacteria to integrate into the local microbiome. Itaconate incorporates into the central metabolism of the biofilm, driving exopolysaccharide production-particularly alginate-which amplifies airway itaconate signaling. This itaconate-alginate interplay limits host immunopathology by enabling pulmonary glutamine assimilation, activating glutaminolysis, and thereby restrain detrimental inflammation caused by the inflammasome. Clinical sample analysis reveals that P. aeruginosa adapts to this metabolic environment through compensatory mutations in the anti-sigma-factor mucA, which restore the succinate-driven bioenergetics and disrupt the metabolic synchrony essential for sustaining disease tolerance.

DOI: https://doi.org/10.1038/s41467-025-59134-1
Shock. 2025 Apr 16.

SVF mediates immunometabolic alterations in burn-induced hypermetabolic adipose tissue via mitochondrial transfer.

Lauar de Brito Monteiro, Shayahati Bieerkehazhi, Ayesha Aijaz, Carly M Knuth, Graham Rix, Ju Hee Lee, Hoon-Ki Sung, Mahmoud Farahat, Marc G Jeschke.

   ABSTRACT: Adipose tissue (AT) browning promotes systemic alterations in energy expenditure as a response to catecholamine-induced hypermetabolism in severe burn trauma. The AT is composed of the stromal vascular fraction (SVF) and adipocytes. SVF contains a vast population of immune cells that maintain AT homeostasis. Despite evidence that local immune cell accumulation contributes to hypermetabolism, the underlying mechanism of persistent browning response is not known. Thus, we hypothesized that a specific cellular communication between adipocytes and SVF can mediate the severe metabolic alterations associated with hypermetabolism. Therefore, we used a murine burn model to show that post-burn hypermetabolism compromises mitochondria respiration and alters the immune cell profile of the AT-SVF. We found that adipocyte-derived signals promote metabolic reprogramming and inflammatory responses by SVF after burns in both mice and humans. Interestingly, adipocytes transfer mitochondria to cells in the SVF including different immune cells (macrophages, T cells, B cells) uptake mitochondria from adipocytes. Such data was replicated in human samples as well. These results indicate that adipocytes play a major role in immunometabolic reprogramming following severe burns through crosstalk with the adipose immune cell population. Therefore, targeting immune cell metabolism restoration is a potential strategy to mitigate the detrimental effects of post-burn hypermetabolism on systemic energy balance.

Keywords:  Adipose tissue; Browning; Hypermetabolism; Immunometabolism; Inflammation; Mitochondria biology

DOI:  https://doi.org/10.1097/SHK.0000000000002608
Immunol Cell Biol. 2025 Apr 23.

A new method to measure cell metabolism of rare cells in vivo reveals a high oxidative phosphorylation dependence of lung T cells.

Aristeidis Roubanis, Morgane Hilaire, Morgane Le Teuff, Odile Devergne, Tim Sparwasser, Luciana Berod, Benoît L Salomon.

  Regulation of cellular metabolism is a central element governing the fate and function of T cells. However, the in vivo metabolic characteristics of rare cells, such as nonlymphoid tissue T cells, are poorly understood because of experimental limitations. Most techniques measuring cell metabolism require large cell numbers. The recent SCENITH method allows for studying the metabolism of rare cells by flow cytometry. However, this technique requires cells to be isolated and cultured ex vivo, which may alter their metabolism. Here, we propose a new experimental approach, called in vivo SCENITH, to investigate the cellular metabolism of T cells in vivo at a steady state in the spleen and lungs. For this purpose, we administered the metabolic modulators directly in mice, instead of applying these reagents ex vivo, as in the classical SCENITH method. Whereas ex vivo manipulation impacted the viability and phenotype of T cells, this toxic effect was not observed in the in vivo SCENITH. We observed that conventional and regulatory T cells shared similar metabolic profiles. Importantly, whereas spleen T cells used both oxidative phosphorylation and glycolysis, the metabolism of T cells in the lungs was mainly based on oxidative phosphorylation. Finally, metabolic inhibitors that interfere with protein translation and energy availability downregulated Foxp3 expression in regulatory T cells. These results describe an expansion of SCENITH that allows to measure the metabolic profile of rare cells in vivo, revealing a high dependence on oxidative phosphorylation of lung T cells.

Keywords:  Cell metabolism; Foxp3; Treg; in vivo SCENITH; lung T cells

DOI:  https://doi.org/10.1111/imcb.70018
Vet Sci. 2025 Mar 07. pii: 254. [Epub ahead of print]12(3):

Exogenous L-Serine Alleviates Pasteurella multocida-Induced Inflammation by Reprogramming the Transcription and Metabolism of Macrophages.

Fang He, Zhengchun Lang, Yanlan Huang, Yangyang Qiu, Pan Xiong, Nengzhang Li, Guangfu Zhao, Yuanyi Peng.

  P. multocida is notorious for inducing excessive inflammation with high lethality in multiple animals, such as cattle, pigs, and chickens. Our previous study revealed that L-serine was decreased in the lungs of mice infected with P. multocida capsular type A strain CQ2 (PmCQ2), and 2 mg/kg of L-serine could alleviate PmCQ2-induced lung inflammation in vivo, which may largely depend on macrophages. However, the underlying intrinsic alterations remain unknown. Here, we demonstrated that 10 mM of L-serine significantly inhibited the release of inflammatory cytokines (e.g., IL-1β and TNF-α) by blocking inflammasome activation (including NALP1, NLRP3, NLRC4, AIM2, and Caspase-1) in PmCQ2-infected macrophages. Furthermore, the results of RNA-seq and metabonomics revealed that exogenous L-serine supplementation substantially reprogrammed macrophage transcription and metabolism. Mechanically, L-serine reduced inflammatory responses via the inhibition of glycolysis in macrophages based on a seahorse assay. Together, these findings characterize the intrinsic molecular alterations in activated macrophages and provide new targets for modulating P. multocida infection-induced macrophage inflammation.

Keywords:  L-serine; Pasteurella multocida; inflammasome; macrophage; metabolic reprogramming

DOI:  https://doi.org/10.3390/vetsci12030254
Cancer Immunol Res. 2025 Apr 22.

NEDDylation regulates CD8+ T cell metabolism and anti-tumor immunity.

Borja Jimenez-Lasheras, Paloma Velasco-Beltrán, Leire Egia-Mendikute, Lorena Pérez-Gutiérrez, So Young Lee, Ander de Blas, Ana García Del Río, Samanta Romina Zanetti, Asier Antoñana-Vildosola, Adrián Barreira-Manrique, Alexandre Bosch, Jone Etxaniz Díaz de Durana, Endika Prieto-Fernández, Marina Serrano-Maciá, Naroa Goikoetxea-Usandizaga, Mikel Azkargorta, Felix Elortza, Thomas Gruber, Sebastian Peer, Gottfried Baier, Ashwin Woodhoo, María Luz Martínez-Chantar, Asis Palazon.

NEDDylation is a post-translational modification whereby the ubiquitin-like molecule NEDD8 is attached to protein substrates in a process dependent on NEDD8 activating enzyme regulatory subunit (NAE1). NEDDylation is emerging as a regulator of cancer biology, but its precise role in antitumor immunity has not been thoroughly characterized. Here, we study the impact of NEDDylation in CD8+ T cell-mediated antitumor responses. Analysis of publicly available single-cell RNA sequencing databases revealed that CD8+ tumor-infiltrating lymphocytes (TILs) showed increased expression of NEDD8 during their differentiation into effector memory cells. In vitro activation of mouse and human CD8+ T cells drove the upregulation of the NEDDylation enzymatic pathway, resulting in an enrichment of NEDDylated proteins. In vivo tumor challenge assays demonstrated that CD8+ T cells lacking NAE1 (NAE1-KO) exhibited reduced antitumor capability and a less activated phenotype with compromised differentiation into effector cells. Upregulating NEDDylation by knocking out deNEDDylase sentrin-specific protease 8 (SENP8) increased the in vitro cytotoxic capability of CD8+ CAR T cells. In addition, LC MS/MS proteomic analyses of NAE1-KO CD8+ T cells and CD8+ T cells treated with the NEDDylation inhibitor MLN4924, showed a pronounced impairment in metabolic pathways, including glycolysis and oxidative phosphorylation. In this context, we validated lactate dehydrogenase A, α-enolase and hexokinase 1, which are relevant glycolytic enzymes, as NEDD8 targets. In line with this, NEDDylation-deficient CD8+ T cells demonstrated reduced transcription, protein expression and enzymatic activity of lactate dehydrogenase. In summary, we uncover NEDDylation as a critical regulator of CD8+ T cell-mediated antitumor immunity.

DOI: https://doi.org/10.1158/2326-6066.CIR-24-0127
Trends Cancer. 2025 Apr 22. pii: S2405-8033(25)00094-9. [Epub ahead of print]

Mitochondrial transfer drives immune evasion in tumor microenvironment.

Qiang Cai, Xiaojun Cai, Quazi T H Shubhra.

  Tumors subvert T cell metabolism through diverse mechanisms. Ikeda et al. reveal mitochondrial transfer as a tumor-driven immune evasion strategy, where cancer cells deliver dysfunctional mitochondria to T cells, impairing metabolism and inducing exhaustion. These findings highlight mitochondrial dynamics as a promising therapeutic target to improve immunotherapy outcomes.

Keywords:  T cell exhaustion; cancer immunotherapy; mitochondrial transfer; tumor microenvironment

DOI:  https://doi.org/10.1016/j.trecan.2025.04.002
Immunology. 2025 Apr 23.

Obesity-Induced Metabolic Priming Exacerbates SARS-CoV-2 Inflammation.

Gustavo Gastão Davanzo, Bianca Gazieri Castelucci, Gabriela Fabiano de Souza, Stéfanie Primon Muraro, Larissa Menezes Dos Reis, Isabella Bonilha de Oliveira, José Luís Fachi, João Victor Virgilio-da-Silva, Marcelo Rodrigues Berçot, Mariane Font Fernandes, Sarah de Oliveira, Nathalia Vitoria Pereira Araujo, Guilherme Ribeiro, Gisele de Castro, Webster Leonardo Guimarães Costa, Adriana Leandra Santoro, Gabriela Flavia Rodrigues-Luiz, Helison Rafael P do Carmo, Ikaro Breder, Marcelo A Mori, Alessandro S Farias, Daniel Martins-de-Souza, Joseph W Guarnieri, Douglas C Wallace, Marco Aurélio Ramirez Vinolo, José Luiz Proença-Módena, Afshin Beheshti, Andrei C Sposito, Pedro M Moraes-Vieira.

  Despite the early recognition that individuals living with obesity are more prone to develop adverse outcomes during COVID-19, the mechanisms underlying these conditions are still unclear. During obesity, an accumulation of free fatty acids (FFAs) in the circulation promotes low-grade inflammation. Here, we show that FFAs induce epigenetic reprogramming of monocytes, exacerbating their inflammatory profile after SARS-CoV-2 infection, a mechanism named metabolic-primed immunity. Monocytes from people with obesity or primed with palmitate, a central component of circulating FFAs, presented elevated viral load and higher gene expression of IL-6. Palmitate-primed monocytes upregulate fatty acid oxidation and FFAs entry into the mitochondria. FFA-derived acetyl-CoA is then converted into citrate, exiting the mitochondria and is used to support H3K18 histone acetylation, which regulates IL-6 accessibility. Ingestion of palm oil by lean and healthy individuals increased circulating FFAs levels and was sufficient to exacerbate the inflammatory profile of monocytes upon SARS-CoV-2 infection. Our findings demonstrate that obesity-derived FFAs induce the metabolic priming of monocytes, which exacerbates the inflammatory response observed in people with severe COVID-19.

Keywords:  COVID‐19; inflammation; innate immunity; monocyte; obesity

DOI:  https://doi.org/10.1111/imm.13934
Front Bioeng Biotechnol. 2025 ;13 1557021

Autofluorescence lifetime imaging classifies human B and NK cell activation state.

Rebecca L Schmitz, Jeremiah M Riendeau, Kelsey E Tweed, Peter Rehani, Kayvan Samimi, Dan L Pham, Isabel Jones, Elizabeth M Maly, Emmanuel Contreras Guzman, Matthew H Forsberg, Ankita Shahi, Lucia Hockerman, Jose M Ayuso, Christian M Capitini, Alex J Walsh, Melissa C Skala.

  New non-destructive tools with single-cell resolution are needed to reliably assess B cell and NK cell function for applications including adoptive cell therapy and immune profiling. Optical metabolic imaging (OMI) is a label-free method that measures the autofluorescence intensity and lifetime of the metabolic cofactors NAD(P)H and FAD to quantify metabolism at a single-cell level. Here, we demonstrate that OMI can resolve metabolic changes between primary human quiescent and IL-4/anti-CD40 activated B cells and between quiescent and IL-12/IL-15/IL-18 activated NK cells. We found that stimulated B and NK cells had an increased proportion of free compared to protein-bound NAD(P)H, a reduced redox state, and produced more lactate compared to control cells. The NAD(P)H mean fluorescence lifetime decreased in the stimulated B and NK cells compared to control cells. Random forest models classified B cells and NK cells according to activation state (CD69+) based on OMI variables with an accuracy of 93%. Our results show that autofluorescence lifetime imaging can accurately assess B and NK cell activation in a label-free, non-destructive manner.

Keywords:  B cells; Immune activation; NK cells; autofluorescence; imaging

DOI:  https://doi.org/10.3389/fbioe.2025.1557021
Front Immunol. 2025 ;16 1548509

Glucose deprivation and identification of TXNIP as an immunometabolic modulator of T cell activation in cancer.

Agathe Dubuisson, Adèle Mangelinck, Samantha Knockaert, Adrien Zichi, Etienne Becht, Wendy Philippon, Sandra Dromaint-Catesson, Manon Fasquel, Fabien Melchiore, Nicolas Provost, Dawid Walas, Hélène Darville, Jean-Pierre Galizzi, Céline Lefebvre, Véronique Blanc, Vincent Lombardi.

   Background: The ability of immune cells to rapidly respond to pathogens or malignant cells is tightly linked to metabolic pathways. In cancer, the tumor microenvironment (TME) represents a complex system with a strong metabolism stress, in part due to glucose shortage, which limits proper T cell activation, differentiation and functions preventing anti-tumor immunity.
Methods: In this study, we evaluated T cell immune reactivity in glucose-restricted mixed lymphocyte reaction (MLR), using a comprehensive profiling of soluble factors, multiparametric flow cytometry and single cell RNA sequencing (scRNA-seq).
Results: We determined that glucose restriction potentiates anti-PD-1 immune responses and identified thioredoxin-interacting protein (TXNIP), a negative regulator of glucose uptake, as a potential immunometabolic modulator of T cell activation. We confirmed TXNIP downregulation in tumor infiltrating T cells in cancer patients. We next investigated the implication of TXNIP in modulating immune effector functions in primary human T cells and showed that TXNIP depletion increased IFN-γ secretion and tumor cell killing.
Conclusions: TXNIP is at the interface between immunometabolism and T cell activation and could represent a potential target for immuno-oncology treatments.

Keywords:  T cells activation; TXNIP; cancer immunotherapy; glucose deprivation; mixed lymphocyte reaction; single-cell RNA-sequencing; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1548509
Cell Commun Signal. 2025 Apr 22. 23(1): 191

Glucose- and glutamine-driven de novo nucleotide synthesis facilitates WSSV replication in shrimp.

Cong-Yan Chen, Chih-Ling Chen, Yen Siong Ng, Der-Yen Lee, Shih-Shun Lin, Chien-Kang Huang, Ramya Kumar, Han-Ching Wang.

   BACKGROUND: Viruses rely on host metabolism to complete their replication cycle. White spot syndrome virus (WSSV), a major pathogen in shrimp aquaculture, hijacks host metabolic pathways to fulfill its biosynthetic and energetic needs. Previous studies have demonstrated that WSSV promotes aerobic glycolysis (Warburg effect) and glutaminolysis during its replication stage (12 hpi). Therefore, glucose and glutamine serve as crucial metabolites for viral replication. Additionally, de novo nucleotide synthesis, including the pentose phosphate pathway and purine/pyrimidine synthesis, is significantly activated during WSSV infection. However, the precise association between WSSV and host glucose and glutamine metabolism in driving de novo nucleotide synthesis remains unclear. This study aimed to investigate the involvement of glucose and glutamine in nucleotide metabolism during WSSV replication and to elucidate how WSSV reprograms these pathways to facilitate its pathogenesis.
METHODS: To assess changes in metabolic flux during WSSV replication, LC-ESI-MS-based isotopically labeled glucose ([U-13C] glucose) and glutamine ([A-15N] glutamine) were used as metabolic tracers in in vivo experiments with white shrimp (Litopenaeus vannamei). The in vivo experiments were also conducted to measure the expression and enzymatic activity of genes involved in nucleotide metabolism. Additionally, in vivo dsRNA-mediated gene silencing was employed to evaluate the roles of these genes in WSSV replication. Pharmacological inhibitors targeting the Ras-PI3K-Akt-mTOR pathway were also applied to investigate its regulatory role in WSSV-induced nucleotide metabolic reprogramming.
RESULTS: The metabolite tracking analysis confirmed that de novo nucleotide synthesis was significantly activated at the WSSV replication stage (12 hpi). Glucose metabolism is preferentially reprogrammed to support purine synthesis, while glutamine uptake is significantly increased and contributes to both purine and pyrimidine synthesis. Consistently, gene expression and enzymatic activity analyses, along with gene silencing experiments, indicated the critical role of de novo nucleotide synthesis in supporting viral replication. However, while the inhibition of the Ras-PI3K-Akt-mTOR pathway suggested its involvement in regulating nucleotide metabolism, no consistent effect on WSSV replication was observed, suggesting the presence of alternative regulatory mechanisms.
CONCLUSION: This study demonstrates that WSSV infection induces specific metabolic reprogramming of glucose and glutamine utilization to facilitate de novo nucleotide synthesis in shrimp. These metabolic changes provide the necessary precursors for nucleotide synthesis, supporting WSSV replication and pathogenesis. The findings offer novel insights into the metabolic strategies employed by WSSV and suggest potential targets for controlling WSSV outbreaks in shrimp aquaculture.

Keywords:  Pentose phosphate pathway; Warburg effect; White shrimp; White spot syndrome virus; de novo nucleotide metabolism; in vivo stable-isotope tracing metabolomics

DOI:  https://doi.org/10.1186/s12964-025-02186-z
EBioMedicine. 2025 Apr 22. pii: S2352-3964(25)00152-5. [Epub ahead of print]115 105708

The metabolic dialogue between intratumoural microbes and cancer: implications for immunotherapy.

Yingheng Situ, Pengpeng Zhang, Cangang Zhang, Aimin Jiang, Nan Zhang, Lingxuan Zhu, Weiming Mou, Zaoqu Liu, Hank Z H Wong, Jian Zhang, Quan Cheng, Anqi Lin, Peng Luo.

  The tumour microenvironment (TME) exerts a profound influence on cancer progression and treatment outcomes. Recent investigations have elucidated the crucial role of intratumoural microbiota and their metabolites in shaping the TME and modulating anti-tumour immunity. This review critically assesses the influence of intratumoural microbial metabolites on the TME and cancer immunotherapy. We systematically analyse how microbial-derived glucose, amino acid, and lipid metabolites modulate immune cell function, cytokine secretion, and tumour growth. The roles of specific metabolites, including lactate, short-chain fatty acids, bile acids, and tryptophan derivatives, are comprehensively examined in regulating immune responses and tumour progression. Furthermore, we investigate the potential of these metabolites to augment the efficacy of cancer immunotherapies, with particular emphasis on immune checkpoint inhibitors. By delineating the mechanisms through which microbial metabolites influence the TME, this review provides insights into novel microbiome-based therapeutic strategies, thereby highlighting a promising frontier in personalised cancer medicine.

Keywords:  Immune checkpoint inhibitors; Immunotherapy; Intratumoural microbiota; Metabolites; Tumour microenvironment

DOI:  https://doi.org/10.1016/j.ebiom.2025.105708
Cell Rep. 2025 Apr 24. pii: S2211-1247(25)00396-1. [Epub ahead of print]44(5): 115625

Loss of neurofibromin induces inflammatory macrophage phenotypic switch and retinal neovascularization via GLUT1 activation.

Yusra Zaidi, Rebekah Tritz, Nida Zaidi, Faisal Nabi, Syed Adeel H Zaidi, Abdelhakim Morsy, Valerie Harris, Rilee Racine, Farlyn Z Hudson, Zsuzsanna Bordan, Simone Kennard, Robert Batori, Yuqing Huo, Gabor Csanyi, Eric J Belin de Chantemèle, Kecheng Lei, Nicholas M Boulis, David J Fulton, Rizwan Hasan Khan, Ruth B Caldwell, Brian K Stansfield.

  Persons with neurofibromatosis type 1 (NF1) exhibit enhanced glucose metabolism, which is replicated in Nf1-mutant mice. Inflammatory macrophages invest NF1-associated tumors, and targeting macrophages appears efficacious in NF1 models. Inflammatory macrophages rely on glycolysis to generate ATP; thus, identifying whether neurofibromin, the protein encoded by NF1, controls glucose metabolism in macrophages is therapeutically compelling. Using neurofibromin-deficient macrophages and macrophage-specific Nf1-knockout mice, we demonstrate that neurofibromin complexes with glucose transporter-1 (GLUT1) to restrain its activity and that loss of neurofibromin permits Akt2 to facilitate GLUT1 translocation to the membrane. In turn, glucose internalization and glycolysis are upregulated and provoke reparative (MIL4) macrophages to undergo an inflammatory phenotypic switch. Inflammatory MLPSIFNγ macrophages and inflammatory-like MIL4 macrophages invest the perivascular stroma of tumors and induce pathologic angiogenesis in macrophage-specific Nf1-knockout mice. These studies identify a mechanism for the enhanced glycolysis associated with NF1 and provide a novel therapeutic target for NF1.

Keywords:  Akt2; CP: Immunology; CP: Metabolism; glucose transporter-1; glucose uptake; glycolysis; inflammation; macrophages; neurofibromin; pathological neovascularization

DOI:  https://doi.org/10.1016/j.celrep.2025.115625
Research (Wash D C). 2025 ;8 0679

Metabolic Homeostasis of Immune Cells Modulates Cardiovascular Diseases.

Mohan Li, Xiaolei Sun, Linqi Zeng, Aijun Sun, Junbo Ge.

Recent investigations into the mechanisms underlying inflammation have highlighted the pivotal role of immune cells in regulating cardiac pathophysiology. Notably, these immune cells modulate cardiac processes through alternations in intracellular metabolism, including glycolysis and oxidative phosphorylation, whereas the extracellular metabolic environment is changed during cardiovascular disease, influencing function of immune cells. This dynamic interaction between immune cells and their metabolic environment has given rise to the novel concept of "immune metabolism". Consequently, both the extracellular and intracellular metabolic environment modulate the equilibrium between anti- and pro-inflammatory responses. This regulatory mechanism subsequently influences the processes of myocardial ischemia, cardiac fibrosis, and cardiac remodeling, ultimately leading to a series of cardiovascular events. This review examines how local microenvironmental and systemic environmental changes induce metabolic reprogramming in immune cells and explores the subsequent effects of aberrant activation or polarization of immune cells in the progression of cardiovascular disease. Finally, we discuss potential therapeutic strategies targeting metabolism to counteract abnormal immune activation.

DOI: https://doi.org/10.34133/research.0679
Nat Microbiol. 2025 Apr 23.

MAVS is a sensor of fumarate during antiviral immunity.

Yukun Min, Luke A J O'Neill.

DOI: https://doi.org/10.1038/s41564-025-01991-z
Annu Rev Immunol. 2025 Apr;43(1): 343-366

Protein Synthesis and Metabolism in T Cells.

Linda V Sinclair, Doreen A Cantrell.

  T lymphocytes are essential for immune responses to pathogens and tumors. Their ability to rapidly clonally expand and differentiate to effector cells following infection, and then to curb effector function following infection clearance, is fundamental for adaptive immunity. Proteome remodeling in response to immune activation is a fundamental mechanism that allows T cells to swiftly reprogram for acquisition of effector function and is possible only because antigen receptor- and cytokine-driven signal transduction pathways can trigger massive increases in protein synthesis. Equally, the ability to repress protein synthesis supports a return to quiescence once pathogens are cleared to avoid autoimmunity and to generate memory T cell populations. This review discusses what is known about T cell proteomes and the regulatory mechanisms that control protein synthesis in T cells. The focus is on how this fundamental process is dynamically controlled to ensure immune homeostasis.

Keywords:  Myc; T cells; amino acid transporters; mammalian target of rapamycin complex 1; protein synthesis; translation

DOI:  https://doi.org/10.1146/annurev-immunol-082323-035253
Biochim Biophys Acta Mol Cell Biol Lipids. 2025 Apr 18. pii: S1388-1981(25)00022-8. [Epub ahead of print] 159614

Phosphatidylethanolamine species with n-3 and n-6 fatty acids modulate macrophage lipidome and attenuate responses to LPS stimulation.

Tatiana Maurício, Inês M S Guerra, Marisa Pinho, Tânia Melo, Stefano Bonciarelli, Laura Goracci, Bruno Neves, Rosário Domingues, Pedro Domingues.

  Phospholipids are increasingly recognized as key regulators of biological processes, including macrophage polarization and function. Among these, phosphatidylethanolamine (PE), a major constituent of cell membranes, is pivotal in maintaining cellular structure and function, yet the mechanisms through which native PE species influence macrophage immunometabolism remain largely unexplored. This study investigates the effects of two native PE species, PE 18:0/22:6 and PE 18:0/20:4, on the lipidome of resting and LPS-activated macrophages. Using C18 HPLC-MS/MS, we identified 337 lipid molecular species across 15 lipid subclasses, 332 of which varied significantly among conditions. Both PE 18:0/22:6 and PE 18:0/20:4 supplementation modulated the macrophage lipidome without inducing a pro-inflammatory phenotype under basal conditions. Notably, supplementation with PE 18:0/22:6 and PE 18:0/20:4 significantly increased lipid classes such as PE, PE O-, SM, CL, PG, LPE and PS, producing unique lipid profiles. Pre-treatment with PE 18:0/22:6 and PE 18:0/20:4 partially attenuated LPS-induced lipidomic changes, significantly reducing lipid classes like PC, including PC O- and PC P-, and Cer, which are typically linked to inflammation. While PE 18:0/20:4, from an individual lipid species perspective, may promote certain lipid profiles compatible with pro-inflammatory signaling pathways, particularly under inflammatory conditions, PE 18:0/22:6 seems to foster a lipid profile more supportive of inflammation resolution. This behaviour of PE 18:0/22:6 and PE 18:0/20:4 highlights the intricate complexity of lipid-mediated immunomodulation and emphasizes the critical role of cellular context in determining the functional outcomes of phospholipid supplementation in macrophage lipid metabolism and immune responses.

Keywords:  Inflammation; Lipidomics; Lipopolysaccharide; Macrophages; Mass-spectrometry; Phosphatidylethanolamine

DOI:  https://doi.org/10.1016/j.bbalip.2025.159614
J Virol. 2025 Apr 23. e0026825

LDHA-lactate axis modulates mitophagy inhibiting CSFV replication.

Sen Zeng, Zipeng Luo, Wenhui Zhu, Zhanhui Zhang, Ruibo Zhao, Shuaiqi Zhu, Qi Qiu, Nan Cao, Xinliang Fu, Wenjun Liu, Shuangqi Fan, Cheng Fu.

  Lactate dehydrogenase A (LDHA) plays a crucial role in regulating lactate synthesis in various biological processes. Lactate, a byproduct of glycometabolism, has been recognized as a unique molecule with implications in both metabolism and immunity. Classical swine fever (CSF), caused by the classical swine fever virus (CSFV), is a highly contagious and severe infectious disease that primarily affects pigs. Prior research has shown that CSFV infection disrupts the normal glycolytic process, leading to an accumulation of lactate within the host. Nevertheless, it remains unclear whether there is mutual regulation between the CSFV and LDHA-lactate axis. Here, we have found that CSFV infection increases LDHA expression in vivo and in vitro, which may be attributed to attenuated ISGylation of LDHA. Furthermore, CSFV infection induces L-lactate production via LDHA dependence in vitro. The cellular biology research on LDHA has revealed that LDHA not only localizes to the mitochondria but also inhibits PINK1-Parkin-mediated mitophagy. Through various experimental techniques such as western blot to detect mitophagy marker proteins, laser confocal microscopy to observe the flow of mitophagy, and transmission electron microscopy to assess changes in the number of mitochondria enclosed within autophagosome-like vesicles, it has been discovered that the addition of exogenous lactate can inhibit PINK1-Parkin-mediated mitophagy. Importantly, we have observed that lactate activates the JAK1-STAT1-ISG15 network and suppresses CSFV replication by antagonizing CCCP-induced mitophagy. These results represent the first report on the mechanisms through which the LDHA-lactate axis regulates mitophagy, the JAK-STAT pathway, and CSFV replication. This study provides novel insights into the roles of the LDHA-lactate axis in glycometabolism and viral replication.
IMPORTANCE: This research unveils how CSFV interacts with cellular metabolism through LDHA. By revealing LDHA's dual role and how lactate influences cellular processes during CSFV infection, this study uncovers new pathways for viral replication. These findings not only deepen our understanding of viral-host interactions but also open doors for innovative antiviral strategies centered around manipulating cellular metabolism.

Keywords:  CSFV; JAK-STAT; LDHA; lactate; mitophagy

DOI:  https://doi.org/10.1128/jvi.00268-25
Immunology. 2025 Apr 22.

Human γδ T Cell Function Is Impaired Upon Mevalonate Pathway Inhibition.

Tsz Kin Suen, Burcu Al, Thomas Ulas, Nico Reusch, Harsh Bahrar, Siroon Bekkering, Jaydeep Bhat, Dieter Kabelitz, Joachim L Schultze, Frank L van de Veerdonk, Jeanine Roeters van Lennep, Niels P Riksen, Leo A B Joosten, Mihai G Netea, Katarzyna Placek.

  Vδ2 T cells, a predominant human peripheral γδ T cell population, are a promising candidate for the development of immunotherapies against cancer and infected cells. Aminobisphosphonate drugs, such as zoledronate, are commonly used to expand Vδ2 T cells. Yet, such in vitro generated cells have limited efficacy in the clinic. We found that despite inducing excessive proliferation of Vδ2 T cells, zoledronate impaired their effector function and caused the upregulation of the inhibitory receptor TIM3. This effect was due to the inhibition of mevalonate metabolism and dysregulation of downstream biological processes such as protein prenylation and intracellular signalling. In vitro and in vivo inhibition of mevalonate metabolism with zoledronate, statins, and 6-fluoromevalonate, as well as genetic deficiency of the mevalonate kinase, all resulted in compromised cytokine and cytotoxic molecule production by Vδ2 T cells. Impaired Vδ2 T cell function was accompanied by transcriptome and kinome changes. Our findings reveal the importance of mevalonate metabolism for the proper functioning of Vδ2 T cells. This observation provides important considerations for improving their therapeutic use and has repercussions for patients with statin or aminobisphosphonate treatments.

Keywords:  T cell; cytokines; flow cytometry; human; protein kinases/phophatases

DOI:  https://doi.org/10.1111/imm.13931
Cell Rep. 2025 Apr 21. pii: S2211-1247(25)00381-X. [Epub ahead of print]44(5): 115610

Mitochondrial protein OPA1 is required for the expansion of effector CD8 T cells.

Benjamin A S Willett, Scott B Thompson, Vincent Chen, Anza Dareshouri, Conner L Jackson, Tonya Brunetti, Angelo D'Alessandro, Jared Klarquist, Travis Nemkov, Ross M Kedl.

  Short-lived effector cells are characterized metabolically by a highly glycolytic state, driving energy and biomass acquisition, whereas memory-fated T cells have historically been described as meeting these requirements through mitochondrial metabolism. Here, we show that the mitochondrial protein optic atrophy 1 (OPA1) is critical for rapidly dividing CD8 T cells in vivo, the requirement for which is most pronounced in effector CD8 T cells. More specifically, OPA1 supports proper cell cycle initiation and progression and the viability and survival of CD8 T cells during clonal expansion. Use of mice deficient in the mitochondrial membrane fusion proteins Mitofusin 1 and 2 (MFN1/2) in both in vivo proliferation/differentiation assays and ex vivo metabolic analysis indicates that the requirement for OPA1 during cell division supersedes its role in mitochondrial fusion. We conclude that OPA1 is critical for the generation and accumulation of short-lived effector cells that arise during the response to infection.

Keywords:  CD8; CP: Immunology; Mitofusins; Opa1; T cell; metabolism

DOI:  https://doi.org/10.1016/j.celrep.2025.115610
Nat Commun. 2025 Apr 20. 16(1): 3736

Targeting CD38 immunometabolic checkpoint improves metabolic fitness and cognition in a mouse model of Alzheimer's disease.

Javier María Peralta Ramos, Giulia Castellani, Denise Kviatcovsky, Tommaso Croese, Afroditi Tsitsou-Kampeli, Chiara Burgaletto, Miguel Angel Abellanas, Liora Cahalon, Sarah Phoebeluc Colaiuta, Tomer-Meir Salame, Yael Kuperman, Alon Savidor, Maxim Itkin, Sergey Malitsky, Sharon Ovadia, Shir Ferrera, Limor Kalfon, Shiran Kadmani, Nadra Samra, Rotem Paz, Lior Rokach, Roberto Furlan, Judith Aharon-Peretz, Tzipora C Falik-Zaccai, Michal Schwartz.

Protective immunity, essential for brain maintenance and repair, may be compromised in Alzheimer's disease (AD). Here, using high-dimensional single-cell mass cytometry, we find a unique immunometabolic signature in circulating CD4+ T cells preceding symptom onset in individuals with familial AD, featured by the elevation of CD38 expression. Using female 5xFAD mice, a mouse model of AD, we show that treatment with an antibody directed to CD38 leads to restored metabolic fitness, improved cognitive performance, and attenuated local neuroinflammation. Comprehensive profiling across distinct immunological niches in 5xFAD mice, reveals a high level of disease-associated CD4+ T cells that produce IL-17A in the dural meninges, previously linked to cognitive decline. Targeting CD38 leads to abrogation of meningeal TH17 immunity and cortical IL-1β, breaking the negative feedback loop between these two compartments. Taken together, the present findings suggest CD38 as an immunometabolic checkpoint that could be adopted as a pre-symptomatic biomarker for early diagnosis of AD, and might also be therapeutically targeted alone or in combination with other immunotherapies for disease modification.

DOI: https://doi.org/10.1038/s41467-025-58494-y
Immunobiology. 2025 Apr 21. pii: S0171-2985(25)00036-1. [Epub ahead of print]230(3): 152902

Ureaplasma urealyticum GrpE protein elicits glycolysis-mediated inflammatory responses through TLR2 in macrophages.

Jing Xie, Nan Xie, Chang Liu, Zhemin Huang, Min Du, Hao Hu, Kang Zheng, Jiaofeng Peng, Ranhui Li.

  The pathogenesis of Ureaplasma urealyticum infection is linked to the host inflammatory response; however, the specific molecular mechanisms underlying this phenomenon have not been fully elucidated. GrpE is a chaperonin that accelerates ADP release and ATP binding to DnaK, thereby enhancing the chaperone function of the HSP70 system under stress. However, alternative activities such as pro-inflammatory responses remain poorly understood. In this study, we report that the U. urealyticum GrpE exerts as a cytokine-inducing virulence factor toward macrophages. Using gene-knockout mice and specific inhibitors, we found that GrpE-induced pro-inflammatory cytokine expression was mediated by the TLR2/STAT3 pathway. We also found that glycolysis was essential for this pro-inflammatory response. Mechanistically, GrpE treatment stimulated STAT3-dependent accumulation of citric acid and acetyl-CoA, promoting histone acetylation and potent pro-inflammatory responses. Our results indicate that glycolysis plays a role in the inflammatory response induced by GrpE through the TLR2/STAT3 pathway and contributes to the glycolysis-mediated inflammatory response, offering a fresh understanding of the development of U. urealyticum infection.

Keywords:  Glycolysis; GrpE; Inflammatory response; TLR2; Ureaplasma urealyticum

DOI:  https://doi.org/10.1016/j.imbio.2025.152902
Nat Commun. 2025 Apr 24. 16(1): 3867

DHODH modulates immune evasion of cancer cells via CDP-Choline dependent regulation of phospholipid metabolism and ferroptosis.

Da Teng, Kenneth D Swanson, Ruiheng Wang, Aojia Zhuang, Haofeng Wu, Zhixin Niu, Li Cai, Faith R Avritt, Lei Gu, John M Asara, Yaqing Zhang, Bin Zheng.

The ability of cancer cells to evade immune destruction is governed by various intrinsic factors including their metabolic state. Here we demonstrate that inactivation of dihydroorotate dehydrogenase (DHODH), a pyrimidine synthesis enzyme, increases cancer cell sensitivity to T cell cytotoxicity through induction of ferroptosis. Lipidomic and metabolomic analyses reveal that DHODH inhibition reduces CDP-choline level and attenuates the synthesis of phosphatidylcholine (PC) via the CDP-choline-dependent Kennedy pathway. To compensate this loss, there is increased synthesis from phosphatidylethanolamine via the phospholipid methylation pathway resulting in increased generation of very long chain polyunsaturated fatty acid-containing PCs. Importantly, inactivation of Dhodh in cancer cells promotes the infiltration of interferon γ-secreting CD8+ T cells and enhances the anti-tumor activity of PD-1 blockade in female mouse models. Our findings reveal the importance of DHODH in regulating immune evasion through a CDP-choline dependent mechanism and implicate DHODH as a promising target to improve the efficacy of cancer immunotherapies.

DOI: https://doi.org/10.1038/s41467-025-59307-y
J Invest Dermatol. 2025 Apr 22. pii: S0022-202X(25)00414-2. [Epub ahead of print]

Cholesterol pathway gene variants and reduced keratinocyte cholesterol support a final common druggable pathway in hyperproliferative inflammatory skin diseases.

Melissa Riachi, Dale Bryant, James Ellis, Connor Hughes, Satyamaanasa Polubothu, Ignacio Del Valle Torres, Aimie Sauvadet, Nicole Knöpfel, Noreen Muwanga-Nanyonjo, Sara Barberan Martin, Alicia Bruzos, Gavin Kelly, Enrica Calvani, Susana A Palma-Duran, Mariana Silva Dos Santos, Charlotte Chaloner, Youssef Khalil, Peter Clayton, Philippa Mills, Neil Bulstrode, Nick Dand, Wei-Li Di, Patricia Barral, Michael A Simpson, Jonathan Barker, James C Lee, James Macrae, Veronica A Kinsler.

  Hyperproliferative inflammatory skin disease (HISD) is frequently seen in rare monogenic diseases of cholesterol metabolism and responds to topical cholesterol/statin. We hypothesised that aberrant cholesterol metabolism within keratinocytes could be important in HISD more generally, driven by either immunological or lipid pathway genetic variation. Whilst other epidermal lipids have been well characterised in HISDs, cholesterol and its metabolites have not. Using GCxGC 3D mass spectrometry we find here that primary keratinocytes from diverse monogenic HISDs (Inflammatory Linear Verruvous Epidermal Naevus ILVEN n=14, CHILD syndrome n=2), and from plaque psoriasis (n=2), demonstrate significantly reduced mean cholesterol across all patient groups compared to controls. This striking abnormality appears causally implicated, as treatment in vitro with cholesterol and statin rescues the cellular hyperproliferation. Using SNPsea and burden analysis of large international psoriasis cohorts we go on to show that GWAS hits are significantly enriched in proximity to genes encoding lipid metabolic pathways, and that rare variants in lipid metabolic pathway genes are significantly enriched in psoriasis patients. These data identify a final common pathway of aberrant keratinocyte cholesterol metabolism in HISD, which should be drugged topically to avoid first pass metabolism. In parallel we implicate genetic variation in lipid pathway genes in psoriasis susceptibility, potentially explaining the co-morbidity of abnormal serum lipid profile and psoriasis.

Keywords:  Psoriasis; cholesterol; hyperproliferative inflammatory skin disease; keratinocyte; statin; therapy; topical

DOI:  https://doi.org/10.1016/j.jid.2025.02.157
J Virol. 2025 Apr 22. e0042825

Cholesterol 25-hydroxylase inhibits Newcastle disease virus replication by enzyme activity-dependent and direct interaction with nucleocapsid protein.

Guangmei Zhu, Xianchun Zong, Mengmeng Xiao, Dan Wang, Zhe Xu, Jingtao Hu, Guilian Yang, Yanlong Jiang, Wentao Yang, Haibin Huang, Chunwei Shi, Yan Zeng, Nan Wang, Xin Cao, Jianzhong Wang, Chunfeng Wang.

  Newcastle disease virus (NDV) is a significant enveloped virus within the Paramyxoviridae family, posing a major threat to the global poultry industry. Increasing evidence suggests that cholesterol-25-hydroxylase (CH25H) and its enzymatic product, 25-hydroxycholesterol (25HC), exhibit broad-spectrum antiviral activity properties by modulating lipid metabolism and various signaling pathways. However, the specific role of CH25H in regulating NDV infection and replication remains unclear. In this study, we demonstrate that CH25H significantly inhibits NDV replication by blocking viral entry through its enzymatic product, 25HC. Notably, a catalytic mutant of CH25H (CH25H-M), which lacks hydroxylase activity, still retains partial ability to inhibit NDV replication, suggesting the involvement of an enzyme-independent antiviral mechanism. Furthermore, we found that CH25H interacts with the viral nucleoprotein (NP), leading to a reduction in NP expression and inhibition of viral ribonucleoprotein (RNP) complex activity. These findings reveal that CH25H exerts antiviral effects through both enzyme-dependent and -independent mechanisms, providing new insights into its role in host defense and offering potential targets for the development of antiviral therapies.IMPORTANCECholesterol 25-hydroxylase (CH25H) is a multifunctional host protein that has been implicated in regulating the life cycles of various viruses. As a prototype of paramyxovirus, Newcastle disease virus (NDV) poses a significant threat to the global poultry industry, causing substantial economic losses. Uncovering the mechanisms of NDV-host interactions is crucial for unraveling the viral pathogenesis and the host immune response, which can drive the development of effective antiviral therapies. Here, we demonstrate that CH25H, whose expression is induced upon NDV infection, plays a pivotal role in restricting viral replication. Specifically, CH25H interacts with the viral NP and inhibits the viral RNP activity. These findings expand our understanding of CH25H's antiviral functions and offer new insights into virus-host interactions, providing potential targets for the development of novel antiviral drugs against NDV and related pathogens.

Keywords:  25-hydroxycholesterol; Newcastle disease virus; cholesterol 25-hydroxylase; viral replication

DOI:  https://doi.org/10.1128/jvi.00428-25
BMC Med. 2025 Apr 23. 23(1): 232

Maternal B12 deficiency during pregnancy dysregulates fatty acid metabolism and induces inflammation in human adipose tissue.

Jinous Samavat, Joseph Boachie, Philip G McTernan, Mark Christian, Ponnusamy Saravanan, Antonysunil Adaikalakoteswari.

   BACKGROUND: Adipose tissue (AT) responds to excess calorie intake; however, the deficit in micronutrients accompanied by the modern lifestyle is often overlooked. Micronutrient deficiency in pregnancy, particularly vitamin B12 (B12), is commonly associated with higher adiposity, dyslipidemia, and type 2 diabetes (T2D). Studies have demonstrated that dyslipidemia can trigger pro-inflammatory status. However, the release of the pro-inflammatory factors in a tissue-specific micronutrient deficient environment is unexplored. Therefore, we investigated the role of B12 deficiency on lipid metabolism and inflammatory mediators in both in vitro and ex vivo models including human pre-adipocytes, primary adipocytes, mature human white AT (WAT), and its association with metabolic risk.
METHODS: Paired abdominal subcutaneous and omental WAT (ScWAT and OmWAT) were chosen based on serum B12 (< 150 pM) from 115 Caucasian pregnant women. Human primary Sc adipocytes from women with different BMI (lean, overweight, obese, morbidly obese) and pre-adipocyte cell line (Chub-S7) were differentiated in various concentrations of B12. Serum B12, folate, lipids, cytokines, biochemical parameters, gene expression, intracellular triglyceride (TG), and mitochondrial function were assessed.
RESULTS: In pregnant women with low B12 levels, BMI and serum TG were significantly higher, and high-density lipoprotein (HDL) was lower (p < 0.05). B12 deficiency in both depots of AT correlated with higher expression of genes in fatty acid (FA) synthesis, elongation, desaturation, TG synthesis, and reduced fatty acid oxidation (FAO) (p < 0.05). In vitro adipocytes with low B12 demonstrated that TG synthesis utilizing radiolabeled FA was higher and mitochondrial function was impaired. We also found that the expression of pro-inflammatory cytokines in AT was increased, and circulatory cytokines inversely associated with serum B12 (p < 0.05).
CONCLUSIONS: Our novel data highlights that B12 deficiency dysregulates lipids and induces inflammation in AT and circulation, which could contribute to adipocyte dysfunction exacerbating cardiometabolic risk during pregnancy.

Keywords:  Adipose tissue; Lipid metabolism; Low-grade inflammation; Obesity; Pregnancy; Vitamin B12

DOI:  https://doi.org/10.1186/s12916-025-04056-4