bims-imicid 2025-11-02 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2025–11–02
37 papers selected by
Dylan Gerard Ryan, Trinity College Dublin

Immunometabolism at the crossroads of infection: mechanistic and systems-level perspectives from host and pathogen.
A carbon trail to follow: unveiling itaconate's metabolism in vivo.
Cancer suppresses mitochondrial chaperone activity in macrophages to drive immune evasion.
Blocking Lysine Crotonylation and Aerobic Glycolysis as Targeting Strategy Against mpox Virus Replication.
Quercetin-derived microbial metabolite DOPAC potentiates CD8+ T cell anti-tumor immunity via NRF2-mediated mitophagy.
Itaconate modulates myeloid inflammation in myocardial infarction via metabolic and structural reprogramming.
Glutamine synthetase deficiency enhances CD8 T cell survival and stress resilience in the tumor microenvironment.
Pneumococcal H₂O₂ reshapes mitochondrial function and reprograms host cell metabolism.
Exhausted CD8+ T Cell in HIV Infection Exhibits an Impaired Bioenergetic Metabolism Driven by Mitochondrial Dysfunction.
Lipid-Driven Immunometabolism in Mesenchymal Stromal Cells: A New Axis for Musculoskeletal Regeneration.
Methionine restriction attenuates renal injury by suppressing macrophage polarization via IRF1 downregulation.
African swine fever virus hijacks host pyrimidine metabolism to promote viral replication.
Immunometabolic reprogramming in lung cancer: interplay between immune and stem-like cells in immune checkpoint inhibitor resistance.
Metabolic Hostile Takeover: How Influenza Virus Reprograms Cellular Metabolism for Replication.
Acsbg1 maintains intestinal immune homeostasis and controls inflammation by regulating ST2+ Tregs.
p53-mediated regulation of electron transport chain and nucleotide synthesis during Newcastle disease virus infection.
Metabolic reprogramming in Helicobacter pylori infection: from mechanisms to therapeutics.
Metabolic adaptation of glucose-deprived macrophages involves partial gluconeogenesis.
Pyruvate Dehydrogenase Complex Stimulation with Dichloroacetate May Improve Septic Cardiac Dysfunction.
Metabolomic profiling of host-pathogen interactions: differential effects of Gram-positive and Gram-negative bacterial secretomes on THP-1 macrophage metabolism.
Metabolomic profiling of Burkholderia thailandensis infection of airway epithelial cells provides insights into potential therapeutic targets.
Myeloid-derived suppressor cells inhibit the replication of oncolytic virus by reducing intratumoral arginine levels.
MPC-mediated lactate production drives histone lactylation in dendritic cells to affect tumor progression and immunotherapy.
Dysbiosis modulates CD8+ tissue-resident memory cells through a mechanism requiring polyamine metabolism during HIV infection.
Loss of MFE-2 impairs microglial lipid homeostasis and drives neuroinflammation in Alzheimer's pathogenesis.
Loss of Bcl6 promotes antitumor immunity by activating glycolysis to rescue CD8 T-cell function.
Altered milk tryptophan and tryptophan metabolites in women living with HIV.
Lactic acid improves Treg manufacturing and in vivo function.
Effect of the mitophagy inducer urolithin A on age-related immune decline: a randomized, placebo-controlled trial.
A Legionella pneumophila T4SS effector protein (Ravl) triggers mitochondrial fragmentation through phosphoinositide phosphatase activity.
Hypoxia induces histone clipping and H3K4me3 loss in neutrophil progenitors resulting in long-term impairment of neutrophil immunity.
CTRP6 as a negative regulator of anti-inflammatory M2 macrophage polarization.
Dietary iron deficiency impairs effector function of memory T cells following influenza infection.
The Parkinson's disease-associated LRRK2-G2019S variant restricts serine metabolism, leading to microglial inflammation and dopaminergic neuron degeneration.
Metabolomics reveals the immunomodulation of endophytic fungal exopolysaccharides from Cyclocarya paliurus in RAW264.7 macrophages via MAPK pathway and metabolic reprogramming.
Alloxan attenuates glucosamine-induced NF-κB activation and proinflammatory gene expression under normoglycemic conditions.
YAP-Induced Glycolysis Drives Fibroinflammation and Disrupts Fibroblast Fidelity.

Immunometabolism (Cobham). 2025 Oct;7(4): e00069

Immunometabolism at the crossroads of infection: mechanistic and systems-level perspectives from host and pathogen.

Sunayana Malla, Nabia Shahreen, Rajib Saha.

  The emerging field of immunometabolism has underscored the central role of metabolic pathways in orchestrating immune cell function. Far from being passive background processes, metabolic activities actively regulate key immune responses. Fundamental pathways such as glycolysis, the tricarboxylic acid cycle, and oxidative phosphorylation critically shape the behavior of immune cells, influencing macrophage polarization, T cell activation, and dendritic cell function. In this review, we synthesize recent advances in immunometabolism, with a focus on the metabolic mechanisms that govern the responses of both innate and adaptive immune cells to bacterial, viral, and fungal pathogens. Drawing on experimental, computational, and integrative methodologies, we highlight how metabolic reprogramming contributes to host defense in response to infection. These findings reveal new opportunities for therapeutic intervention, suggesting that modulation of metabolic pathways could enhance immune function and improve pathogen clearance.

Keywords:  adaptive immune cells; bacteria; fungi and pathogens; innate immune cells; virus

DOI:  https://doi.org/10.1097/IN9.0000000000000069
Immunometabolism (Cobham). 2025 Oct;7(4): e00072

A carbon trail to follow: unveiling itaconate's metabolism in vivo.

Denis E Anisov, Sally A Clayton, Maxim A Nosenko.

  The discovery of itaconate as an immunoregulatory metabolite has transformed the field of immunometabolism and opened multiple therapeutic avenues over the past decade. While the immunological functions of itaconic acid have been extensively studied, several aspects of its biochemistry-particularly in vivo utilization pathways-have remained unclear. In a recent study published in Nature Metabolism, Willenbockel et al apply carbon tracing to uncover the metabolic fate of itaconate within the organism. Insights from this work have important implications for understanding the physiological roles of itaconate and for advancing itaconate-based therapeutic strategies.

Keywords:  itaconate metabolism; stable isotope tracing; succinate dehydrogenase

DOI:  https://doi.org/10.1097/IN9.0000000000000072
Nat Immunol. 2025 Oct 29.

Cancer suppresses mitochondrial chaperone activity in macrophages to drive immune evasion.

Haoxin Zhao, Jaeoh Park, Yuzhu Wang, Yi-Ju Chou, Lemin Li, Lydia N Raines, Michael Hsu, Ching-Cheng Lin, Wei Cao, Yuli Ouyang, Heng-Yi Chen, Linghua Zheng, Zihai Li, Alex Y Huang, Ping-Chih Ho, Chan-Wang Jerry Lio, Stanley Ching-Cheng Huang.

Contrary to tumor-infiltrating T cells with dysfunctional mitochondria, tumor-associated macrophages (TAMs) preserve their mitochondrial activity in the nutrient-limited tumor microenvironment (TME) to sustain immunosuppression. Here we identify TNF receptor-associated protein-1 (TRAP1), a mitochondrial HSP90 chaperone, as a metabolic checkpoint that restrains oxidative respiration and limits macrophage suppressive function. In the TME, TRAP1 is downregulated through TIM4-AMPK signaling, and its loss enhances immunoinhibitory activity, limits proinflammatory capacity and promotes tumor immune escape. Mechanistically, TRAP1 suppression augments electron transport chain activity and elevates the α-ketoglutarate/succinate ratio, remodeling mitochondrial homeostasis. The resulting accumulation of α-ketoglutarate further potentiates JMJD3-mediated histone demethylation, establishing transcriptional programs that reinforce an immunosuppressive state. Restoring TRAP1 by targeting TIM4 and JMJD3 reprograms TAMs, disrupts the immune-evasive TME and bolsters antitumor immunity. These findings establish TRAP1 as a critical regulator integrating metabolic and epigenetic control of suppressive TAM function and position the TRAP1 pathway as a promising target for cancer immunotherapy.

DOI: https://doi.org/10.1038/s41590-025-02324-2
Adv Sci (Weinh). 2025 Oct 27. e09148

Blocking Lysine Crotonylation and Aerobic Glycolysis as Targeting Strategy Against mpox Virus Replication.

Pengjun Wei, Zongzheng Zhao, Ruoqi Xu, Qin Yan, Liangzi Jiang, Fuxiao Geng, Yang Gu, Tianjiao Wang, Jing Zhou, Xiao Li, Qin Yan, Chun Lu, Wan Li.

  The global outbreak of mpox caused by the mpox virus (MPXV) in 2022 and 2024 underscores the urgent need to elucidate mechanisms governing viral replication during pathogenesis. Metabolic reprogramming is a conserved hallmark of viral infections, however, the precise mechanisms by which MPXV manipulates host cell metabolism remain unknown. Here, it is demonstrated that MPXV hijacks aerobic glycolysis via lysine crotonylation of its I3 protein, which is essential for MPXV replication. Mechanistically, MYST histone acetyltransferase 1 (MYST1), an acetyltransferase upregulated by MPXV, binds to and catalyzes the crotonylation of I3. The crotonylated I3 interacts with WD-repeat protein 26 (WDR26) to prevent its ubiquitination-dependent degradation, leading to enhanced aerobic glycolysis and promoting MPXV replication. Either pharmacological inhibition of MYST1 using MC4033 or blocking aerobic glycolysis with the glycolytic inhibitors 2-Deoxy-D-glucose (2-DG) or dichloroacetic acid (DCA) effectively suppresses MPXV replication. These findings uncover a novel crotonylation-dependent mechanism through which MPXV reprograms host metabolism to facilitate viral propagation, and identify lysine crotonylation and aerobic glycolysis as potential therapeutic targets against mpox.

Keywords:  I3; MYST1; aerobic glycolysis; crotonylation; mpox virus

DOI:  https://doi.org/10.1002/advs.202509148
Cell Metab. 2025 Oct 24. pii: S1550-4131(25)00395-X. [Epub ahead of print]

Quercetin-derived microbial metabolite DOPAC potentiates CD8+ T cell anti-tumor immunity via NRF2-mediated mitophagy.

Penghu Han, Shuzheng Chu, Jing Shen, Lixiang Li, Yan Zhang, Shiguan Wang, Yatai Chen, Yangchun Ma, Xiaolong Tang, Chao Gao, Xiangyun Zheng, Bowen Xu, Qiong Wang, Detian Yuan, Shiyang Li.

  Quercetin, a dietary flavonol, shows promise in cancer prevention, though its effects on the immune compartment within the tumor microenvironment are not fully understood. Here, we identify 3,4-dihydroxyphenylacetic acid (DOPAC), a microbial metabolite of quercetin, as a critical mediator of its anti-tumor effects in a CD8+ T cell-dependent manner. Mechanistically, DOPAC directly binds to Kelch-like epichlorohydrin-associated protein 1 (KEAP1), disrupting its interaction with nuclear factor erythroid 2-related factor 2 (NRF2) and preventing KEAP1-mediated degradation of NRF2 in CD8+ T cells. Elevated NRF2 transcriptionally enhances the expression of B cell lymphoma 2-interacting protein 3, promoting mitophagy and mitochondrial functionality, which improves CD8+ T cell fitness within the tumor microenvironment. Furthermore, DOPAC synergizes with immune checkpoint blockade to suppress tumor growth. Our findings underscore the role of microbial metabolites of dietary nutrients in modulating anti-tumor immune responses, positioning DOPAC as a promising candidate for cancer immunotherapy.

Keywords:  BNIP3; CD8(+) T cells; DOPAC; NRF2; anti-tumor immunity; microbiota; mitophgagy; quercetin

DOI:  https://doi.org/10.1016/j.cmet.2025.09.010
Genes Genomics. 2025 Oct 30.

Itaconate modulates myeloid inflammation in myocardial infarction via metabolic and structural reprogramming.

Tao Zhang, Ruijinlin Hao, Chuanfu Li, Kun Yang, Lei Zhou.

   BACKGROUND: Acute myocardial infarction (AMI) is a leading cause of mortality worldwide, with sterile inflammation and immune dysregulation driving cardiac injury. Itaconate, a mitochondria-derived immunometabolite synthesized by ACOD1, has emerged as a key regulator of myeloid cell function, exhibiting anti-inflammatory and metabolic effects. However, its role and downstream targets in sterile myocardial inflammation remain poorly understood.
OBJECTIVE: This study aimed to systematically dissect the immunometabolic role of itaconate in AMI by identifying itaconate-responsive genes, uncovering their cell-type specificity and functional dynamics, and evaluating their diagnostic and therapeutic potential.
METHODS: We established a novel systems-level framework that integrates bulk and single-cell/single-nucleus transcriptomics, network pharmacology, machine learning-based feature selection, and molecular docking. This multi-layered strategy was applied to human and murine datasets covering infarcted cardiac tissue and peripheral immune compartments to identify robust, itaconate-responsive immune targets in AMI.
RESULTS: Single-cell data show that ACOD1 induction is disease-specific and characteristic of AMI. And we identified 36 itaconate-associated genes enriched in myeloid populations and dynamically regulated during infarction. Among them, MMP9, TLR2, and ANPEP were consistently prioritized by multiply machine learning algorithms, showed robust diagnostic performance across independent cohorts, and exhibited potential binding to itaconate in silico. Single-cell analyses confirmed spatial and temporal regulation of these targets in infarcted myocardium. Functional analyses revealed that 4-octyl-itaconate (4-OI) induced dose- and context-dependent transcriptional programs in myeloid cells, including NRF2 and ATF3 activation.
CONCLUSIONS: This study identifies a core immunometabolic program downstream of itaconate in myeloid cells and highlights MMP9, TLR2, and ANPEP as key effectors linking metabolic sensing to inflammation and tissue remodeling in AMI. Our integrative approach offers new insights into context-specific immunomodulation and supports the development of metabolite-guided therapeutic strategies for cardiovascular inflammation.

Keywords:  Acute myocardial infarction; Immunometabolism; Itaconate; Machine learning; Myeloid cells

DOI:  https://doi.org/10.1007/s13258-025-01698-9
J Immunol. 2025 Oct 31. pii: vkaf250. [Epub ahead of print]

Glutamine synthetase deficiency enhances CD8 T cell survival and stress resilience in the tumor microenvironment.

Emilie L Fisher-Gupta, Emma S Hathaway, Jeffrey M Perera, Erin Q Jennings, Channing Chi, Allison E Sewell, Spenser H Stone, Jason E Muka, Rachael C Sinard, Joseph A DeCorte, Heidi Chen, John T Wilson, Jens Meiler, Jeffrey C Rathmell.

  Cellular immunotherapy has revolutionized the treatment of hematologic malignancies yet has had limited success in the solid tumor microenvironment (TME). While insufficient nutrients can lead to T cell metabolic stress in the TME, the glutamine antagonist DON can paradoxically enhance antitumor immunity. Because DON inhibits both essential and nonessential enzymes whose impairment may contribute to dose-limiting toxicities, mechanisms underlying DON-induced antitumor activity have remained unclear. Here, we aimed to identify specific DON targets that increase T cell antitumor activity and test if more selective inhibition of glutamine metabolism could replicate the effects of DON with reduced toxicity. CRISPR screening in the TME of DON-relevant glutamine metabolizing enzymes identified some targets that were essential in tumor-infiltrating CD8 T cells, but that tumor-infiltrating CD8 T cells lacking the DON target glutamine synthetase (GS) were enriched. Upon adoptive T cell transfers, GS-deficient CD8+ T cells displayed improved survival, a higher proportion TCF-1+ Tox- stem-like cells, and greater antitumor and memory function. GS converts glutamate to glutamine and GS-deficient cells exhibited increased intracellular glutamate and reduced glutathione levels, which correlated with enhanced mitochondrial respiration and resistance to reactive oxygen species. Pharmacological inhibition of GS reduced tumor burden in multiple orthotopic murine tumor models in a manner dependent on adaptive immunity. Our findings establish GS as a key metabolic regulator of CD8+ T cells stress resilience in the TME. By preserving intracellular glutamate, GS inhibition reprograms T cells for improved survival and function, offering a promising therapeutic strategy to enhance immune-based cancer treatments.

Keywords:  T cell; antitumor immunity; glutamine; glutamine synthetase; immunometabolism

DOI:  https://doi.org/10.1093/jimmun/vkaf250
mBio. 2025 Oct 31. e0201925

Pneumococcal H₂O₂ reshapes mitochondrial function and reprograms host cell metabolism.

Anna Scasny, Babek Alibayov, Ngoc Hoang, Ana G Jop Vidal, Kenichi Takeshita, Consuelo Bautista-Muñoz, Eva Bengten, Antonino Baez, Wei Li, Jonathan Hosler, Kurt Warncke, Kristin S Edwards, Jorge E Vidal.

  Streptococcus pneumoniae (Spn), a primary cause of pneumonia, induces acute lung parenchymal damage through a unique metabolic pathway generating hydrogen peroxide (H₂O₂) as a byproduct. This study demonstrates that Spn-derived H₂O₂, primarily produced by pyruvate oxidase (SpxB), inhibits key tricarboxylic acid (TCA) cycle enzymes (aconitase, glutamate dehydrogenase, and α-ketoglutarate dehydrogenase) in lung epithelial cells, leading to citrate accumulation and diminished NADH production for oxidative phosphorylation. RNA sequencing reveals SpxB-dependent upregulation of glycolytic genes (HIF1A, IER3, HK2, PFKP), restricting pyruvate entry into the TCA cycle and increasing glucose consumption and lactate/acetate production, indicative of a Warburg-like metabolic shift that may enhance bacterial survival. Notably, mitochondrial membrane potential remains largely preserved, with minimal apoptosis despite Spn-induced stress. These findings uncover a novel mechanism of Spn-driven host metabolic reprogramming, highlighting potential therapeutic targets for pneumococcal diseases.IMPORTANCEStreptococcus pneumoniae (Spn) remains a leading cause of community-acquired pneumonia worldwide, yet the mechanisms by which it manipulates host metabolism to promote its survival and pathogenesis are not fully understood. This study reveals a novel metabolic strategy whereby pneumococcus-derived hydrogen peroxide, generated by pyruvate oxidase (SpxB), disrupts the host tricarboxylic acid (TCA) cycle and drives a Warburg-like metabolic shift in lung epithelial cells. By inhibiting key TCA cycle enzymes and rewiring glycolytic gene expression, Spn effectively reprograms host cell metabolism to favor its persistence while minimizing host cell apoptosis and maintaining mitochondrial function. These insights expand our understanding of host-pathogen metabolic interactions and identify potential metabolic vulnerabilities that could be targeted to mitigate tissue damage and improve treatment outcomes in pneumococcal pneumonia.

Keywords:  Streptococcus pneumoniae; Warburg effect; host-pathogen interactions; mitochondrial metabolism; pneumonia

DOI:  https://doi.org/10.1128/mbio.02019-25
Immunology. 2025 Oct 28.

Exhausted CD8+ T Cell in HIV Infection Exhibits an Impaired Bioenergetic Metabolism Driven by Mitochondrial Dysfunction.

Yee Teng Chan, Kar Min Loh, Zhi Ying Phong, Ting Fang Tang, Chun Howe Ng, Alireza Saeidi, Heng Choon Cheong, Yi Ying Cheok, Rong Xiang Ng, Raja Iskandar Shah Raja Azwa, Kian-Kai Cheng, Chung Yeng Looi, Adeeba Kamarulzaman, Reena Rajasuriar, Won Fen Wong.

  In people living with HIV (PLWH), persistent viral replication and antiretroviral therapy (ART)-associated toxicity contribute to T cell exhaustion, characterised by significant metabolic reprogramming that negatively impacts cellular function and longevity. Understanding the metabolic dysregulation in exhausted T cells could unveil novel therapeutic strategies to rejuvenate immune responses in PLWH. This study investigated the prevalence and metabolic gene expression profiles of exhausted CD8+ T cells across three PLWH cohorts: viremic treatment-naïve (TN), viremic treatment-failure (TF) and aviremic treatment-responders (TR). Our analysis revealed that the proportion of exhausted CD8+ T cells (PD1+CD107a-) was markedly higher in viremic TN (5.1%) and TF (4.2%) groups compared to the aviremic TR cohort (2.2%, p < 0.05). Similarly, the percentage of terminally differentiated TEMRA cells (CCR7-CD45RA+) was elevated in TN (38.0%) and TF (44.7%) compared with TR (21.5%, p < 0.05), indicating a higher prevalence of late-stage differentiation and exhaustion in viremic individuals. NanoString analysis revealed a broad downregulation of metabolic genes in exhausted CD8+ T cells from viremic individuals, suggesting a shift toward a metabolically quiescent state akin to naïve T cells. Seahorse analysis revealed impaired mitochondrial respiration in CD8+ T cells from viremic PLWH, characterised by reductions in both ATP-linked respiration and proton leak. Furthermore, we reported that combined treatment with MitoTEMPO and N-acetyl-l-cysteine (NAC) improved mitochondrial function but failed to restore the effector capacity of CD8+ T cells. In summary, this study highlights the defective metabolic programming of exhausted CD8+ T cells in viremic PLWH, underscoring potential metabolic targets for therapeutic intervention.

Keywords:  CD8+ T cell; HIV; T cell exhaustion; metabolic pathways; mitochondria; people living with HIV (PLWH)

DOI:  https://doi.org/10.1111/imm.70054
Int J Mol Sci. 2025 Oct 17. pii: 10117. [Epub ahead of print]26(20):

Lipid-Driven Immunometabolism in Mesenchymal Stromal Cells: A New Axis for Musculoskeletal Regeneration.

Vibha Velur, Patrick C McCulloch, Francesca Taraballi, Federica Banche-Niclot.

  The immunosuppressive and anti-inflammatory potential of mesenchymal stromal cells (MSCs) underpins their therapeutic value in musculoskeletal disorders. However, the underlying mechanisms remain ill-defined. Traditionally associated with immune cells, immunometabolism (the cellular metabolism-immune system interplay) is now recognized as central in a broader range of processes, including tissue homeostasis, repair, and chronic inflammation. Depending on the context and cell type, distinct metabolic pathways (e.g., fatty acid oxidation, lipid mediator biosynthesis) can drive pro-inflammatory/pro-resolving immune phenotypes. This dynamic is salient in musculoskeletal tissues: macrophage polarization, T-cell activation, and MSC immunomodulation are governed by metabolic cues. Emerging evidence highlights lipid-driven immunometabolism as a key player in MSC function, particularly in post-traumatic osteoarthritis (PTOA) and osteoporosis (OP). Unlike immune cells, MSCs rely on distinct metabolic programs (e.g., lipid sensing, uptake, and signaling) to exert context-dependent immunoregulation. In PTOA, persistent inflammation triggers lipid-centric metabolic pathways, enhancing MSC-driven immunomodulation and therapeutic outcomes. In OP, low-grade inflammation and altered lipid metabolism impair bone regeneration, modulating lipid-driven routes that can restore MSC osteogenic function and influence osteoclast precursors. This review explores how lipid-derived mediators and signaling contribute to MSCs' immunosuppressive capacity, positioning lipid immunometabolism as a novel axis for rebalancing the inflamed joint microenvironment and encouraging musculoskeletal regeneration.

Keywords:  immunometabolism; inflammation; lipids; mesenchymal stromal cells; osteoporosis; post-traumatic osteoarthritis; tissue regeneration

DOI:  https://doi.org/10.3390/ijms262010117
Food Funct. 2025 Oct 27.

Methionine restriction attenuates renal injury by suppressing macrophage polarization via IRF1 downregulation.

Wang Yi, Liu Song, Zhishui Chen.

Ischemia-reperfusion injury is a leading cause of acute kidney injury and delayed graft function following kidney transplantation. Macrophages are key mediators of ischemia-reperfusion injury-induced inflammation and tissue remodelling; however, the metabolic mechanisms underlying their activation remain poorly defined. In this study, we demonstrate that methionine restriction impaired the polarization of bone marrow-derived macrophages toward both M1 and M2 phenotypes. Mechanistically, methionine restriction led to decreasing H3K4me3 enrichment at the Irf1 promoter, thereby downregulating IRF1 expression and impairing macrophage polarization. Dietary methionine restriction reduced the infiltration of inflammatory macrophages, alleviated tubular damage, and attenuated early interstitial fibrosis in a mouse model of renal ischemia-reperfusion injury. These findings identify methionine metabolism as a key immunometabolism checkpoint in renal ischemia-reperfusion injury and suggest that dietary methionine restriction may serve as a potential therapeutic strategy to attenuate inflammation and fibrosis in ischemic kidney injury.

DOI: https://doi.org/10.1039/d5fo04229a
J Virol. 2025 Oct 31. e0098525

African swine fever virus hijacks host pyrimidine metabolism to promote viral replication.

Zebu Song, Yilin Chen, Hui Guo, Guihong Zhang, Lang Gong, Zezhong Zheng.

  African swine fever (ASF) is a highly contagious disease of pigs caused by the African swine fever virus (ASFV), posing a significant threat to global swine production. As an obligate intracellular parasite, ASFV relies on host metabolic networks to fulfill its replication requirements. However, the precise mechanisms by which it manipulates nucleotide metabolism remain unclear. In this study, untargeted metabolomic analysis of ASFV-infected porcine alveolar macrophages revealed significant perturbations in purine and pyrimidine metabolism, glycolysis, the pentose phosphate pathway (PPP), and the glutamate and aspartate metabolic pathways. Functional validation demonstrated that ASFV depends on de novo pyrimidine biosynthesis for viral genome replication. Notably, ASFV employs a dual strategy to sustain the supply of nucleotide precursors: (i) it hijacks the PPP to generate ribose-5-phosphate and NADPH for redox balance, and (ii) it enhances glutamine uptake and catabolism to provide the nitrogen and carbon needed for nucleotide biosynthesis and tricarboxylic acid cycle replenishment. Furthermore, although aspartate is essential for pyrimidine synthesis, ASFV circumvents dependence on extracellular aspartate by activating a cytosolic GOT1-mediated synthesis pathway. Collectively, these findings elucidate how ASFV reprograms host nucleotide metabolism to support its replication, offering new insights into virus-host metabolic interactions and identifying potential targets for antiviral therapy.IMPORTANCEAfrican swine fever (ASF) is a devastating disease that causes substantial economic losses in the global pig industry. This study demonstrates that the African swine fever virus (ASFV) reprograms host cell metabolism to produce the essential building blocks required for its replication. Specifically, ASFV manipulates host nucleotide biosynthetic pathways to secure both the substrates for DNA synthesis and the reducing power necessary to mitigate oxidative stress. Elucidating these metabolic interactions not only deepens understanding of ASFV pathogenesis but also highlights promising metabolic targets for antiviral therapy. By elucidating how ASFV hijacks nucleotide biosynthesis within infected cells, our findings pave the way for innovative strategies to combat ASF.

Keywords:  African swine fever virus; aspartate; glutamine; metabolic hijacking; pyrimidine metabolism

DOI:  https://doi.org/10.1128/jvi.00985-25
J Transl Med. 2025 Oct 29. 23(1): 1190

Immunometabolic reprogramming in lung cancer: interplay between immune and stem-like cells in immune checkpoint inhibitor resistance.

Ji-Yong Sung, Eui Tae Kim.



Keywords:  Cancer stem-like cells (CSCs); Immune checkpoint inhibitor (ICI) resistance; Immunometabolism; Immunosuppressive niche; Metabolic plasticity; Metabolic reprogramming; Tumor microenvironment (TME)

DOI:  https://doi.org/10.1186/s12967-025-07244-1
Viruses. 2025 Oct 17. pii: 1386. [Epub ahead of print]17(10):

Metabolic Hostile Takeover: How Influenza Virus Reprograms Cellular Metabolism for Replication.

Xianfeng Hui, Xiaowei Tian, Shihuan Ding, Ge Gao, Xin Zhao, Jiyan Cui, Yiru Hou, Tiesuo Zhao, Hui Wang.

  Influenza viruses are adept at hijacking host cellular machinery to facilitate their replication and propagation. A critical aspect of this hijacking involves the reprogramming of host cell metabolism. This review summarizes current findings on how influenza virus infection alters major metabolic pathways, including enhanced glycolysis, suppression of oxidative phosphorylation, diversion of TCA cycle intermediates for biosynthesis, and upregulation of lipid and amino acid metabolism. Key nutrients like glucose, glutamine, and serine are redirected to support viral RNA synthesis, protein production, and membrane formation. Moreover, these metabolic changes also modulate host immune responses, potentially aiding in immune evasion. We highlight the role of transcription factors such as SREBPs in lipid synthesis and the impact of one-carbon metabolism on epigenetic regulation. Finally, we discuss how targeting virus-induced metabolic shifts, using agents like 2-deoxyglucose or fatty acid synthesis inhibitors, offers promising avenues for antiviral intervention, while emphasizing the need for selective approaches to minimize harm to normal cells.

Keywords:  amino acid metabolism; antiviral strategies; cellular metabolism; glycolysis; influenza virus; lipid biosynthesis

DOI:  https://doi.org/10.3390/v17101386
Mucosal Immunol. 2025 Oct 26. pii: S1933-0219(25)00114-X. [Epub ahead of print]

Acsbg1 maintains intestinal immune homeostasis and controls inflammation by regulating ST2+ Tregs.

Martina Palatella, Friederike Kruse, Honglei Ji, Alina K Loriani Fard, Maike Becker, Carolin Daniel, Maria Rohm, Jochen Huehn.

  The immune balance in mucosal tissues depends on a delicate interplay between inflammatory T helper 17 (Th17) cells and immunosuppressive regulatory T cells (Tregs). But what happens when this balance is disturbed? In this study, we uncovered a critical role for acyl-CoA synthetase bubblegum family member 1 (Acsbg1) in shaping Th17and Treg dynamics. Using Acsbg1-deficient mice, we show that while its absence does not disrupt homeostasis under steady-state conditions, it significantly alters Treg populations, particularly in gut-associated tissues. Under high-fat diet-induced metabolic stress, Acsbg1-deficient mice display mild metabolic changes but maintain systemic immune and metabolic function, indicating that Acsbg1 is dispensable for metabolic adaptation in vivo. However, upon infection with Citrobacter rodentium, these mice exhibit excessive Th1/Th17-driven inflammation and impaired resolution, accompanied by a strong reduction in IL-10-producing and ST2+ Treg subsets. The impact is even more striking in an adoptive transfer colitis model, where Acsbg1-deficient Tregs fail to control inflammation, resulting in severe colitis and tissue damage. Our findings identify Acsbg1 as a key regulator of ST2+ Treg function and a central player in mucosal immune homeostasis, highlighting its potential as a therapeutic target for inflammatory bowel disease and colorectal cancer.

Keywords:  Acsbg1; Colitis; Fatty acid metabolism; Mucosal immunology; Th17 cell; Tregs

DOI:  https://doi.org/10.1016/j.mucimm.2025.10.009
J Virol. 2025 Oct 31. e0157625

p53-mediated regulation of electron transport chain and nucleotide synthesis during Newcastle disease virus infection.

Changrun Zhao, Ning Tang, Jing Wang, Yang Qu, Lei Tan, Cuiping Song, Xusheng Qiu, Ying Liao, Tingrong Luo, Chan Ding, Yingjie Sun.

  Mitochondria and their electron transport chain (ETC) constitute the central machinery for cellular energy metabolism and biosynthetic regulation. Disruption of the ETC leads to reactive oxygen species (ROS) production and metabolic imbalance, but its precise role in viral replication and infection remains to be elucidated. In this study, we used Newcastle disease virus (NDV), an important avian pathogen and a promising oncolytic virus, as a model to explore its relationship with cellular mitochondrial metabolism. We demonstrate that NDV infection induces varying degrees of mitochondrial fragmentation, membrane potential dissipation, and ROS production, especially in p53-null H1299 cells compared to p53-wild-type A549 cells. ETC impairment restricts NDV replication primarily by limiting aspartate and pyrimidine nucleotide biosynthesis, rather than through ROS-mediated cytotoxicity or energy depletion. Notably, NDV replication in p53-null cells is highly sensitive to ETC complexes I and III inhibition, which can be rescued by exogenous aspartate or uridine supplementation. Mechanistically, p53 serves as a metabolic buffer, protecting mitochondrial function and maintaining precursor availability during viral infection. These findings elucidate the selective and differential utilization of mitochondrial ETC components by NDV and reveal that p53 status shapes cellular susceptibility to NDV-induced metabolic stress. Our work highlights mitochondrial metabolism and p53 as potential targets for antiviral and oncolytic strategies against NDV.IMPORTANCEThis study uncovers the intricate relationship between Newcastle disease virus (NDV) infection and host cell mitochondrial metabolism, with a particular emphasis on the pivotal regulatory role of p53. As both an important avian pathogen and a promising oncolytic virus, NDV disrupts mitochondrial function and the electron transport chain, leading to p53-mediated alterations in cellular energy metabolism and redox homeostasis. Our findings not only deepen the understanding of NDV-mitochondria interactions but also highlight the central role of p53 in viral infection and oncolytic mechanisms. These insights provide a theoretical foundation and novel therapeutic targets for antiviral and anticancer strategies based on p53 or mitochondrial pathways.

Keywords:  NDV; electron transport chain; mitochondrial metabolism; nucleotide synthesis; p53; reactive oxygen species

DOI:  https://doi.org/10.1128/jvi.01576-25
Front Cell Infect Microbiol. 2025 ;15 1678044

Metabolic reprogramming in Helicobacter pylori infection: from mechanisms to therapeutics.

Tong Liu, Xuelin Zhao, Ting Cai, Wei Li, Minglin Zhang.

  Helicobacter pylori (H. pylori), a key gastric mucosal pathogen, causes chronic gastritis, peptic ulcers, and gastric cancer. H. pylori remodel the gastric microenvironment through metabolic reprogramming to drive pathogenesis. CagA+ strains disrupt lipid metabolism, increasing non-alcoholic fatty liver disease, cardiovascular, and Alzheimer's risks via PPAR interference, GBA1 demethylation, and altered FABP1/APOA1 expression, reversible by eradication. In glucose metabolism, H. pylori promote carcinogenesis via Lonp1-induced glycolysis, PDK1/Akt dysregulation, and HKDC1/TGF-β1/MDFI-mediated epithelial-mesenchymal transition, while exacerbating high-fat diet-induced dysbiosis. Infection manipulates macrophage immunometabolism. Bacterial utilization of host L-lactate through H. pylori gene clusters enables proliferation, gland colonization, and immune evasion by suppressing complement activation and TNF/IL-6 secretion. Lactate-targeting strategies show therapeutic promise. Amino acid dysregulation involves H. pylori biotin protein ligase (HpBPL)-mediated catabolism and γ-glutamyl transpeptidase-induced glutathione hydrolysis, depleting antioxidants while inducing dendritic cell tolerance. branched-chain amino acids accumulation activates mTORC1, and cystine-glutamate transporter inhibition with miR-30b upregulation exacerbates mucosal damage, forming a self-sustaining "metabolic reprogramming-immune evasion-tissue destruction" cycle. These mechanisms collectively enable H. pylori to propel gastric carcinogenesis, highlighting metabolism-targeted interventions as future solutions. This review summarizes how H. pylori remodel the gastric microenvironment and drives pathogenesis by manipulating host lipid, glucose, lactate, and amino acid metabolism.

Keywords:  Helicobacter pylori; amino acid metabolism; gastric carcinogenesis; glucose metabolism; lactate metabolism; lipid metabolism; metabolic reprogramming

DOI:  https://doi.org/10.3389/fcimb.2025.1678044
Proc Natl Acad Sci U S A. 2025 Nov 04. 122(44): e2419568122

Metabolic adaptation of glucose-deprived macrophages involves partial gluconeogenesis.

Katharina Schindlmaier, Theresa Haitzmann, Visnja Bubalo, Barbara Konrad, Joseph Jelwan, Gabriele Bluemel, Sonja Rittchen, Vanessa Jäger, Michael A Dengler, Luka Brcic, Jörg Lindenmann, Leigh M Marsh, Thomas O Eichmann, Alexander Kirchmair, Zlatko Trajanoski, Julia Kargl, Cristina Muñoz-Pinedo, Katharina Leithner.

  Macrophages are recruited to sites of infection contributing to the killing of bacteria, but also to malignant tumors, where they promote angiogenesis and suppress antitumor immune responses. The metabolic microenvironment in tumors is frequently depleted of important nutrients such as glucose. Here, we investigated metabolic adaptation strategies of macrophages to glucose deprivation using stable isotopic tracing. Lactate production was decreased, potentially indicating a reduction of glycolysis. In contrast, the contribution of glutamine to the tricarboxylic acid cycle via α-ketoglutarate and reductive carboxylation were increased. Moreover, gluconeogenesis, the reverse pathway of glycolysis, was activated in glucose-deprived macrophages, proceeding partially to the generation of glycolytic intermediates and glycerol-3-phosphate. The partial gluconeogenesis pathway was abrogated in human and murine macrophages lacking the initial gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PCK2, mitochondrial isoform). Partial gluconeogenesis was higher in anti-inflammatory, interleukin-4-stimulated compared to proinflammatory, interferon-γ/lipopolysaccharide-stimulated macrophages. Single-cell analysis and immunostaining revealed expression of PCK2 in macrophages from both lung cancer and normal lung. Low glucose conditions only partially modulated macrophage phenotypes, leading to reduced CD80 surface marker levels in proinflammatory, and enhanced vascular endothelial growth factor expression in anti-inflammatory macrophages. Our study reveals partial gluconeogenesis in glucose-deprived macrophages and shows that this versatile type of immune cells exhibits remarkable metabolic flexibility.

Keywords:  glucose deprivation; glycolysis; macrophages; metabolism; partial gluconeogenesis

DOI:  https://doi.org/10.1073/pnas.2419568122
Shock. 2025 Oct 31.

Pyruvate Dehydrogenase Complex Stimulation with Dichloroacetate May Improve Septic Cardiac Dysfunction.

Lane M Smith, Yu Tin Lin, Chelsey S Mertens, Manal L Zabalawi, David L Long, Barbara K Yoza, Anderson O Cox, Boone M Prentice, Peter W Stacpoole, Charles E McCall.

   BACKGROUND: Cardiomyopathy is a common complication of sepsis that contributes to increased morbidity and mortality. However, the molecular mechanisms underlying septic cardiomyopathy are poorly understood. Dichloroacetate (DCA) improves mitochondrial respiration and survival in a mouse model of sepsis by inhibiting pyruvate dehydrogenase kinase which inactivates pyruvate dehydrogenase (PDH) through phosphorylation of its subunits. In this study, we explore the role of DCA in septic cardiac dysfunction using a murine sepsis model.
METHODS: Cecal ligation and puncture (CLP) was performed in mice to investigate molecular and echocardiographic response to sepsis. DCA was administered to test the effects of PDH activation on cardiac performance during early and late sepsis and myocardial metabolic substrate production. Matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry was used to reveal spatial alterations in metabolism.
RESULTS: CLP significantly increased phosphorylation of the PDH E1α subunit (PDH inactivation), and DCA treatment reduced PDH E1α phosphorylation (PDH activation) to baseline without affecting total PDH E1α levels. Administration of DCA at the time of CLP improved cardiac preload and stroke volume without affecting cardiac contractility at 12 h after CLP. However, there was a significant increase in cardiac contractility at 30 h after DCA administration independent of cardiac loading conditions. This improved cardiac function after DCA administration was associated with a trend toward decreased production of metabolic intermediates such as ketogenic amino acids, succinate, and palmitoyl carnitine. Imaging mass spectrometry revealed an increase in itaconate expression upon CLP that was mitigated by DCA administration.
CONCULSIONS: Our findings revealed that sepsis decreased PDH activity in cardiac tissue. Rebalancing PDH activity with DCA improved cardiac performance after CLP. While imaging mass spectrometry identified changes in itaconate concentration and enabled detection of tricarboxylic acid cycle metabolites, further investigation is necessary to determine whether DCA is an effective therapeutic agent for septic cardiomyopathy.

Keywords:  Cardiomyopathy; infection; inflammation; metabolism; shock

DOI:  https://doi.org/10.1097/SHK.0000000000002642
RSC Adv. 2025 Oct 22. 15(48): 40607-40618

Metabolomic profiling of host-pathogen interactions: differential effects of Gram-positive and Gram-negative bacterial secretomes on THP-1 macrophage metabolism.

Alaa Abuawad, Manuel Romero, Sandra Martinez Jarquin, Amir M Ghaemmaghami, Dong-Hyun Kim.

Infectious diseases present substantial health and economic challenges worldwide. The increasing prevalence of multidrug-resistant bacteria in both community and hospital settings has emerged as a global health issue that necessitates innovative strategies for prompt diagnosis and treatment. Metabolomics, which provides comprehensive insights into the biochemical alterations of cellular phenotypes, has emerged as a valuable approach for studying host-pathogen interactions and identifying novel therapeutic targets. In this study, untargeted liquid chromatography-mass spectrometry (LC-MS)-based metabolite profiling was employed to investigate the differential effects of the secretome from Gram-positive S. aureus SH1000 and Gram-negative P. aeruginosa PAO1 on THP-1 macrophages. The results revealed that both bacterial secretomes modulate several key metabolic pathways, including alanine, aspartate and glutamate metabolism; sphingolipid metabolism; glycine and serine metabolism; glycolipid metabolism; and tryptophan metabolism. Distinct metabolic trends were observed between the two secretomes: S. aureus induced an accumulation of asparagine and l-formylkynurenine, alongside depletion of glycine-related intermediates (e.g. sarcosine, guanidinoacetate), whereas P. aeruginosa altered creatine levels and reduced asparagine and l-kynurenine. Notably, shared effects were also identified, with both secretomes demonstrating similar significant effects (FDR < 0.05 and VIP > 1) on arginine and proline metabolism in THP-1 macrophages. These findings highlight both shared and unique pathogen-specific metabolic responses, offering preliminary insights into host metabolic reprogramming triggered by exemplar Gram-positive and Gram-negative bacteria. These results provide a foundation for future studies to explore bacterial pathogenesis and to identify therapeutic strategies against resistant infections.

DOI: https://doi.org/10.1039/d4ra07202b
mSystems. 2025 Oct 31. e0061125

Metabolomic profiling of Burkholderia thailandensis infection of airway epithelial cells provides insights into potential therapeutic targets.

Daniel J Hicks, Nicole Aiosa, Anupama Sinha, Olakunle A Jaiyesimi, Steven S Branda, Neha Garg.

  Burkholderia pseudomallei, a gram-negative saprophyte that causes melioidosis, has been classified as a potential bioweapon, posing a serious global threat. Metabolic re-wiring, production of virulence effectors, evasion/suppression of host defenses, and modification of host cell functions constitute important mechanisms in the pathogenesis of infection. Elucidating the metabolism during intracellular growth of the pathogen is critical for learning the mechanisms by which infection is accomplished. Currently, the metabolic activities associated with, and potentially mediating, host-pathogen interactions during infection are not well understood, but recent advances in untargeted mass spectrometry-based metabolomics methods are enabling the narrowing of this knowledge gap. Here, we used untargeted metabolomics analysis to identify polar metabolites produced by Burkholderia thailandensis E264 (a surrogate for B. pseudomallei) and airway epithelial cells (the murine cell line LA-4) during the intracellular stage of infection. Pathway analysis of annotated metabolites that differed in abundance in mock-challenged versus B. thailandensis-challenged host cells revealed changes in the activity of a diverse set of metabolic pathways that could be targeted to combat Burkholderia infections. These include pathways that mediate metabolic processes occurring in both the pathogen and host (e.g., polyamine biosynthesis, NAD+ [nicotinamide adenine dinucleotide] metabolism, and the citric acid cycle), as well as several pathogen-specific pathways (peptidoglycan biosynthesis, ornithine lipid production, and quorum sensing-regulated secondary metabolites). The observed shift in the metabolome shows commonalities with other gram-negative pathogens during infection. Our results provide insight into the changes in metabolism associated with Burkholderia infection and reveal several promising targets for therapeutic interventions.IMPORTANCEBurkholderia pseudomallei is the causative agent of infectious disease, namely melioidosis. When inhaled, Burkholderia pseudomallei causes severe respiratory infections. Due to the potential for severe airborne infections, it is classified as a Tier 1 biothreat agent. The intrinsic antibiotic resistance and increased global prevalence necessitate the development of alternative treatments. Infection triggers a metabolic "arms race" between host and pathogen, where both organisms dramatically alter their metabolism to outcompete one another. By studying these changes, one can identify new therapeutic targets for drug discovery and better understand the mechanisms pathogens use to establish and maintain infection. We performed an untargeted metabolomics analysis of murine epithelial cells co-cultured with Burkholderia thailandensis, a surrogate for Burkholderia pseudomallei, to identify the metabolic shifts that occur during intracellular infection. Using these analyses, we propose several pathways and therapeutic interventions to enable pathogen clearance.

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

DOI:  https://doi.org/10.1128/msystems.00611-25
Mol Ther Oncol. 2025 Dec 18. 33(4): 201066

Myeloid-derived suppressor cells inhibit the replication of oncolytic virus by reducing intratumoral arginine levels.

Parker Dryja, Erica B Flores, Mee Y Bartee, Viswanathan Palanisamy, Eric Bartee.

  Oncolytic virotherapy uses replication-competent viruses to treat various solid tumors. While much of the clinical efficacy of oncolytic virotherapy is mediated by anti-tumor T cell responses, most of these therapies still rely on the in vivo replication of the viral agents within infected tumor cells. Understanding the fundamental mechanisms that govern this replication therefore remains essential to the clinical application of these therapies. As viruses, oncolytic agents rely entirely on host metabolites and resources for their propagation. To address this gap in knowledge, we asked which cells impacted the intratumoral replication of oncolytic myxoma virus during treatment of B16F10 melanomas. Our results demonstrate that myxoma replication is potently restricted by the presence of intratumoral arginase-1+ myeloid-derived suppressor cells, which prevent the spread of oncolytic infection by catabolizing intratumoral arginine supplies. Additionally, either pharmacological depletion of these cells or genetic ablation of their arginase-1 expression markedly improves intratumoral myxoma infection and enhances the therapeutic efficacy of viruses. Collectively, these results suggest that the clinical application of oncolytic viruses is likely to be impacted by the unique metabolic state of the tumor microenvironment and that myeloid-derived suppressor cell-mediated depression of arginine within tumors may play a critical role in suppressing these treatments.

Keywords:  MT: Regular Issue; arginine metabolism; immunotherapy; myxoma virus; oncolytic virotherapy

DOI:  https://doi.org/10.1016/j.omton.2025.201066
Cell Mol Life Sci. 2025 Oct 28. 82(1): 371

MPC-mediated lactate production drives histone lactylation in dendritic cells to affect tumor progression and immunotherapy.

Bin Zhang, Anran Xu, Haowei Wang, Wei Yan, Qing Zhang, Shuang Wang.

  Lactate is an abundant oncometabolite in the tumor microenvironment (TME). Lactate driven by metabolic reprogramming leads to acidic microenvironment formation to promote the immune evasion of tumor cells and reduce the effectiveness of immunotherapy for patients with tumors. The expression of mitochondrial pyruvate carrier (MPC) is crucial for pyruvate metabolism, and its dysregulation can lead to the formation of an acidic microenvironment caused by excessive lactic acid. However, the impact of MPC on tumor metabolic processes and biological behavior, as well as how lactate impacts immunosuppression, remains unclear. Here, we found that MPC1 and MPC2, two subunits of MPC, were downregulated in patients with colorectal cancer (CRC). Co-overexpression of MPC1 and MPC2 decreased lactate levels and inhibited cell proliferation, migration and invasion in vitro and tumor growth in vivo in the setting of CRC. Knockdown of MPC1 or MPC2 increased lactate levels and promoted the proliferation, migration and invasion of CRC cells. Mechanistically, the accumulation of lactate promotes the elevation of histone lactylation levels, and MPC regulates the expression of CD33, a marker of dendritic cell (DC) maturation, via histone lactylation, decreasing CD8+ T cell functions. In addition, the overexpression of MPC increased the therapeutic effect of the anti-PD-1 antibody. Our findings reveal that MPC downregulation-mediated lactate production impacts DC maturation via histone lactylation-dependent transcriptional regulation to impair CD8+ T cell responses, suggesting that targeting MPC could enhance immunotherapy efficacy by modulating the TME.

Keywords:  CD33; Colorectal cancer; Dendritic cell; Histone lactylation; Mitochondrial pyruvate transporter carrier

DOI:  https://doi.org/10.1007/s00018-025-05881-9
iScience. 2025 Nov 21. 28(11): 113679

Dysbiosis modulates CD8+ tissue-resident memory cells through a mechanism requiring polyamine metabolism during HIV infection.

Sangeetha Jayaraman, Shanmuga Mahalingam, Michael M Lederman, Fady Faddoul, Andre Paes da Silva, Robert Asaad, Leah P Shriver, Natarajan Bhaskaran, Elizabeth Schneider, Grace Heine, Tobi Taylor, Samantha Horne, Ashley Yoon, Zihan Zhu, Liangliang Zhang, Adam Burgener, Gina Lewin, Pushpa Pandiyan.

  Polyamines play crucial roles in modulating T lymphocyte functions. Here, we demonstrate that the oral mucosa of people living with HIV (PLWH), characterized by active polyamine metabolic pathways, exhibits significantly diminished IFN-γ expression and reduced abundance of CD8+ tissue-resident memory (TRM) cells. Salivary 16S rRNA sequencing revealed elevated levels of Fusobacteria, negatively correlating with the levels of CD8+ TRM-like cells in PLWH. In vitro experiments showed that Fusobacterium nucleatum (FN) produced putrescine, which is known to be enriched in PLWH mucosa. Polyamines, HIV infection, and FN led to EIF-5A hypusination, diminished IFN-γ expression in CD8+ T cells, which impaired the proliferation of TRM-like cells in tonsil organoid cells. The inhibition of polyamine synthesis and EIF-5A hypusination restored IFN-γ expression and TRM-like cells. Collectively, these results highlight an essential role of polyamines in the critical interplay between oral resident microbiota, immunometabolic regulation, and immune competence during chronic viral infections.

Keywords:  Health sciences; Immunology; Medical specialty; Medicine

DOI:  https://doi.org/10.1016/j.isci.2025.113679
Nat Aging. 2025 Oct 29.

Loss of MFE-2 impairs microglial lipid homeostasis and drives neuroinflammation in Alzheimer's pathogenesis.

Min Gao, Jing Bai, Fangzhou Lou, Yang Sun, Zhikai Wang, Xiaojie Cai, Yan Li, Fengjiao Zhang, Jihuan Liang, Xiangxiao Li, Yue Wu, Ziyang Zhang, Li Fan, Xinping Jin, Honglin Wang.

Dysregulated lipid metabolism promotes persistent microglial activation and neuroinflammation in Alzheimer's disease (AD), but the underlying pathogenic mechanisms remain to be elucidated, and druggable targets remain to be identified. Here we found that multifunctional enzyme type 2 (MFE-2), the key enzyme regulating fatty acid β-oxidation in the peroxisome, was downregulated in the microglia of humans with AD and AD model mice. Microglia-specific ablation of MFE-2 drove microglial abnormalities, neuroinflammation and Aβ deposition in AD models. Mechanistically, MFE-2 deficiency facilitated lipid accumulation, resulting in excessive arachidonic acid, mitochondrial reactive oxygen species and proinflammatory cytokine production by microglia. The compound 3-O-cyclohexane carbonyl-11-keto-β-boswellic acid (CKBA) bound to MFE-2 and restored MFE-2 levels, ameliorating AD pathology by inhibiting microglial overactivation. Collectively, our data revealed a pathogenic role of microglia with impaired lipid metabolism in AD and identified MFE-2 as a druggable target of CKBA, which restores its expression and has therapeutic potential for treating AD.

DOI: https://doi.org/10.1038/s43587-025-00976-1
Life Sci Alliance. 2026 Jan;pii: e202503335. [Epub ahead of print]9(1):

Loss of Bcl6 promotes antitumor immunity by activating glycolysis to rescue CD8 T-cell function.

Fangkun Luan, Yunqiao Li, Jia Ning, Jenny Tuyet Tran, Tanya R Blane, Raag Bhargava, Zhe Huang, Changchun Xiao, David Nemazee.

T cells are one of the most powerful weapons to fight cancer; however, T-cell exhaustion and dysfunction restrict their long-lasting function in antitumor immunity. B-cell lymphoma 6 (BCL6) has many functions in CD8 T cells; however, it is unclear how it regulates the effector function and exhaustion of CD8 cells. Overall, a low level of BCL6 mRNA in human cancer samples is associated with better outcomes, but high expression of BCL6 is specifically observed in cytotoxic CD8 T cells. We found that BCL6 deficiency in activated CD8 T cells enhanced tumor repression in multiple mouse models. More IL-2-expressing CD8 T cells and reduced proportions of exhausted or dysfunctional CD8 T cells were detected within tumors when Bcl6 was knocked out upon T-cell activation. Glycolysis was promoted, and GLUT3 expression was derepressed in BCL6-deficient CD8 T cells. The BCL6 inhibitor Fx1 promoted antitumor immunity in a T cell-dependent manner. These findings suggest a novel pathway to restore effector function of CD8 T cells by changing their energy use pathways to facilitate long-term tumor resistance.

DOI: https://doi.org/10.26508/lsa.202503335
Nat Commun. 2025 Oct 28. 16(1): 9437

Altered milk tryptophan and tryptophan metabolites in women living with HIV.

Nicole H Tobin, Fan Li, Wentao Zhu, Kathie G Ferbas, John W Sleasman, Daniel Raftery, Louise Kuhn, Grace M Aldrovandi.

Children born to women living with HIV (WLWH) suffer increased morbidity and, in low-income settings, have two to three times the mortality of infants born to women without HIV. The basis for this increase remains elusive. In low-income settings, breastfeeding is recommended because health benefits outweigh the risk of transmission, especially when maternal antiretroviral therapy is provided. We profile the milk metabolome of 326 women with and without HIV sampled longitudinally for 18 months postpartum using global metabolomics. We identify perturbations in several metabolites, including tryptophan, dimethylarginine, and a recently discovered antiviral ribonucleotide, that are robustly associated with maternal HIV infection. Quantitative tryptophan and kynurenine levels in both milk and plasma reveal that these perturbations reflect systemic depletion of tryptophan and alterations in tryptophan catabolism in WLWH. Finally, we validate these signatures of maternal HIV infection in an independent cohort of healthier WLWH. Taken together, our findings demonstrate that milk tryptophan content and availability decrease among WLWH, which may indicate perturbations in milk tryptophan catabolism. The link between this perturbation and the increased morbidity and mortality of children born to WLWH merits further investigation.

DOI: https://doi.org/10.1038/s41467-025-64566-w
Mol Ther Methods Clin Dev. 2025 Dec 11. 33(4): 101600

Lactic acid improves Treg manufacturing and in vivo function.

Karoliina Tuomela, Emily S Y Leong, Manjurul Haque, Sonya Mangat, Vivian C W Fung, Rosa V Garcia, Anne-Sophie Archambault, Dominic A Boardman, Ramon I Klein Geltink, Majid Mojibian, Megan K Levings.

  Adoptive cell therapy using regulatory T cells (Tregs) is a promising approach to suppress immune responses in autoimmunity and transplantation, but it is challenging to expand pure and optimally suppressive cells. Lactic acid (LA) is associated with enhanced Treg function in tumors so we hypothesized that it may be beneficial during Treg expansion. We found that addition of LA at day 3 post-stimulation onwards improved viability and purity, increased glycolysis upon re-stimulation, and led to superior suppressive function. In Tregs expressing chimeric antigen receptors (CARs) specific for HLA-A2, LA not only enhanced viability and purity but also significantly reduced tonic signaling-associated expression of exhaustion-associated markers (PD-1, TIM-3, LAG-3, TOX, and BLIMP-1). The effects of LA were not fully recapitulated by either pH-neutral lactate or low pH. In immunodeficient mouse models of chronic stimulation and xenogeneic graft-versus-host disease, LA-conditioned human Tregs demonstrated enhanced stability, reduced exhaustion marker expression, and improved efficacy. Thus, LA has a multimodal effect on human polyclonal and CAR Treg purity, viability, and function, representing a method to generate an optimal Treg product for cell therapy.

Keywords:  autoimmunity; cell manufacture; exhaustion; lactate; lactic acid; metabolism; regulatory T cell; transplantation

DOI:  https://doi.org/10.1016/j.omtm.2025.101600
Nat Aging. 2025 Oct 31.

Effect of the mitophagy inducer urolithin A on age-related immune decline: a randomized, placebo-controlled trial.

Dominic Denk, Anurag Singh, Herbert G Kasler, Davide D'Amico, Julia Rey, Lucía Alcober-Boquet, Johanna M Gorol, Christoph Steup, Ritesh Tiwari, Ryan Kwok, Rafael J Argüello, Julie Faitg, Kathrin Sprinzl, Stefan Zeuzem, Valentina Nekljudova, Sibylle Loibl, Eric Verdin, Chris Rinsch, Florian R Greten.

Mitochondrial dysfunction and stem cell exhaustion contribute to age-related immune decline, yet clinical interventions targeting immune aging are lacking. Recently, we demonstrated that urolithin A (UA), a mitophagy inducer, expands T memory stem cells (TSCM) and naive T cells in mice. In this randomized, double-blind, placebo-controlled trial, 50 healthy middle-aged adults received oral UA (1,000 mg day-1) or placebo for 4 weeks; time points of analysis were baseline and day 28. Primary outcomes were phenotypical changes in peripheral CD3+ T cell subsets and immune metabolic remodeling. UA expanded peripheral naive-like, less terminally exhausted CD8+ cells (treatment difference 0.50 percentage points; 95% CI = 0.16 to 0.83; P = 0.0437) while also increasing CD8+ fatty acid oxidation capacity (treatment difference = 14.72 percentage points; 95% confidence interval (CI) = 6.46 to 22.99; P = 0.0061). Secondary outcomes included changes in plasma cytokine levels (IL-6, TNF, IL-1β, IL-10), immune populations assessed via flow cytometry, immune cell function, and mitochondrial content. Analysis revealed augmented mitochondrial biogenesis in CD8+ cells, increased peripheral CD56dimCD16bright NK cells, and nonclassical CD14loCD16hi monocytes in UA-treated participants, as well as improved activation-elicited TNF secretion in T cells and bacterial uptake by monocytes. Exploratory single-cell RNA sequencing demonstrated UA-driven transcriptional shifts across immune populations, modulating pathways linked to inflammation and metabolism. These findings indicate that short-term UA supplementation modulates human immune cell composition and function, supporting its potential to counteract age-related immune decline and inflammaging. ClinicalTrials.gov registration number: NCT05735886 .

DOI: https://doi.org/10.1038/s43587-025-00996-x
Int J Biol Macromol. 2025 Oct 28. pii: S0141-8130(25)09170-6. [Epub ahead of print] 148613

A Legionella pneumophila T4SS effector protein (Ravl) triggers mitochondrial fragmentation through phosphoinositide phosphatase activity.

Ruiling Zhang, Meiling Zhang, Xiaoyu Li, Zhifang Lu, Chen Song, Yangchun Du, Chelsy Chesterman, Laura van Staalduinen, Youjun Wang, Hairun Pei, Zongchao Jia, Jimin Zheng.

  Upon ingestion by macrophages, Legionella pneumophila hijacks host membrane trafficking by decorating Legionella-containing vacuoles (LCV), thereby escaping lysosomal degradation. L. pneumophila is dependent on the T4SS effector proteins to recruit mitochondria or promote mitochondria association with the LCV, which induces mitochondrial fragmentation and ultimately alters mitochondrial metabolism. However, a T4SS effector protein implicated in mitochondrial recruitment and fragmentation has yet to be identified. Here, we report the crystal structure of RavL, a L. pneumophila T4SS effector protein. The RavL N-terminus has a canonical mitochondrial targeting sequence. We show that RavL localizes to the mitochondrial membrane and induces fragmentation to disrupt mitochondrial function, ultimately triggering apoptosis in THP-1 macrophages. Further biochemical analysis reveals that RavL is a phosphatidylinositol polyphosphate 5-phosphatase that specifically hydrolyzes the D5 phosphate of PtdIns(4)P, which is derived from PtdIns(4,5)P2. Taken together, our study has identified a novel atypical phosphoinositide phosphatase, RavL, which actively exploits phosphoinositide metabolism to disturb mitochondrial function, thereby promoting bacterial infection.

Keywords:  Effector protein; Mitochondrial fragmentation; PI phosphatase; Type IV secretion system

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.148613
Nat Immunol. 2025 Nov;26(11): 1903-1915

Hypoxia induces histone clipping and H3K4me3 loss in neutrophil progenitors resulting in long-term impairment of neutrophil immunity.

PHOSP-COVID Study Collaborative Group

The long-term impact of systemic hypoxia resulting from acute respiratory distress syndrome (ARDS) on the function of short-lived innate immune cells is unclear. We show that patients 3-6 months after recovering from ARDS have persistently impaired circulating neutrophil effector functions and an increased susceptibility to secondary infections. These defects are linked to a widespread loss of the activating histone mark H3K4me3 in genes that are crucial for neutrophil activities. By studying healthy volunteers exposed to altitude-induced hypoxemia, we demonstrate that oxygen deprivation alone causes this long-term neutrophil reprogramming. Mechanistically, mouse models of systemic hypoxia reveal that persistent loss of H3K4me3 originates in proNeu and preNeu progenitors within the bone marrow and is linked to N-terminal histone 3 clipping, which removes the lysine residue for methylation. Thus, we present new evidence that systemic hypoxia initiates a sustained maladaptive reprogramming of neutrophil immunity by triggering histone 3 clipping and H3K4me3 loss in neutrophil progenitors.

DOI: https://doi.org/10.1038/s41590-025-02301-9
Immunometabolism (Cobham). 2025 Oct;7(4): e00070

CTRP6 as a negative regulator of anti-inflammatory M2 macrophage polarization.

Jeevotham Senthil Kumar, Emma Kempton, Muhammad Zubair Mehboob, Dingbo Lin, Xia Lei.

   Background: Chronic low-grade inflammation in adipose tissue, primarily driven by macrophages, plays a central role in obesity pathophysiology. C1q/TNF-related protein 6 (CTRP6), a member of the CTRP family, has emerged as a key regulator of this inflammatory process. Here, we demonstrate that CTRP6 expression is upregulated in adipose tissue macrophages during obesity, where it acts as a potent modulator of macrophage polarization by suppressing M2 polarization.
Methods: In RAW264.7 macrophages, we distinguished M1 and M2 polarization, induced by lipopolysaccharide (LPS) + interferon-gamma (IFNγ) and interleukin (IL)-4, respectively, by selecting two marker genes for each polarization type from a set of five widely used markers, based on a time-course analysis. We then assessed the effects of recombinant CTRP6 protein treatment on M1 and M2 polarization. Finally, we validated our findings in primary bone marrow-derived macrophages (BMDMs).
Results: In naïve RAW264.7 macrophages, recombinant CTRP6 protein upregulated M1 marker genes (Tnf, Nos2) while downregulating M2 markers (Mrc1, Pparg). During M1 polarization induced by LPS+IFNγ, CTRP6 treatment had no significant effect. However, during IL-4-induced M2 polarization, CTRP6 not only enhanced M1 markers but also strongly suppressed M2 markers by inhibiting anti-inflammatory signal transducer and activator of transcription 6 (STAT6) signaling and relieving the inhibition of pro-inflammatory ERK1/2 signaling. Additionally, CTRP6 impaired mitochondrial activity, favoring glycolysis in macrophages. Importantly, these effects were serum-independent and confirmed in BMDMs.
Conclusions: Since endogenous CTRP6 expression in BMDMs is upregulated by M1 polarization inducers, it may further hinder inflammation resolution, even in the presence of IL-4 during tissue repair, establishing it as a key driver of adipose tissue inflammation in obesity.

Keywords:  CTRP6; M2 macrophage polarization; adipose tissue; inflammation; negative regulator

DOI:  https://doi.org/10.1097/IN9.0000000000000070
J Immunol. 2025 Oct 29. pii: vkaf291. [Epub ahead of print]

Dietary iron deficiency impairs effector function of memory T cells following influenza infection.

Marissa C Bradley, Tolani Aliyu, Joshua Gray, Tianci Guan, Francesca La Carpia, Emma Idzikowski, Isaac J Jensen, Sheila Bandyopadhyay, Rebecca Guyer, Kalpana Pethe, Eldad A Hod, Thomas J Connors.

The establishment of memory T cell responses is critical to protection against pathogens and is influenced by the conditions under which memory formation occurs. Iron is an essential micronutrient for multiple immunologic processes and nutritional deficiency is a common problem worldwide. Despite its prevalence, the impact of nutritional iron deficiency on the establishment of memory T cell responses is poorly understood. In this study we investigate the impact of nutritional iron deficiency on the generation, phenotype, and function of memory T cell responses using a murine model of dietary iron modulation in the context of influenza infection. Iron deficient mice have decreased systemic iron levels and develop significant anemia. Increased T cell expression of the transferrin receptor (CD71) is seen in iron deficient mice at baseline. During primary influenza infection, iron deficient mice experience increased weight loss but mount antigen specific T cells responses. Following recovery from infection, influenza specific memory T cells formed under iron deficient conditions are functionally impaired, most notably within the lung. Importantly, the ability to produce interferon γ (IFN-γ) and tumor necrosis factor α (TNF-α) remains impaired in CD8+ T cells despite co-culture with iron replete dendritic cells. These results establish a critical effect of nutritional iron deficiency on T cell memory development and function.

DOI: https://doi.org/10.1093/jimmun/vkaf291
J Neuroinflammation. 2025 Oct 27. 22(1): 244

The Parkinson's disease-associated LRRK2-G2019S variant restricts serine metabolism, leading to microglial inflammation and dopaminergic neuron degeneration.

Henry Kurniawan, Sarah L Nickels, Alise Zagare, Elisa Zuccoli, Isabel Rosety, Gemma Gomez-Giro, Enrico Glaab, Jens C Schwamborn.

  A growing body of evidence implicates inflammation as a key hallmark in the pathophysiology of Parkinson's disease (PD), with microglia playing a central role in mediating neuroinflammatory signaling in the brain. However, the molecular mechanisms linking microglial activation to dopaminergic neuron degeneration remain poorly understood. In this study, we investigated the contribution of the PD-associated LRRK2-G2019S mutation to microglial neurotoxicity using patient-derived induced pluripotent stem cell (iPSC) models. We found that LRRK2-G2019S mutant microglia exhibited elevated activation markers, enhanced phagocytic capacity, and increased secretion of pro-inflammatory cytokines such as TNF-α. These changes were associated with metabolic dysregulation, including upregulated glycolysis and impaired serine biosynthesis. In 3D midbrain organoids, these overactivated microglia resulted in dopaminergic neuron degeneration. Notably, treating LRRK2-G2019S microglia with oxamic acid, a glycolysis inhibitor, attenuated microglial inflammation and reduced neuronal loss. Our findings underscore the link between metabolic targeting in microglia and dopaminergic neuronal loss in LRRK2-G2019S mutation, and highlight a potential strategy that warrants further preclinical evaluation.

Keywords:  Glycolysis; IPSC; LRRK2-G2019S; Metabolism; Microglia; Organoids; Parkinson’s disease; Serine

DOI:  https://doi.org/10.1186/s12974-025-03577-2
Int Immunopharmacol. 2025 Oct 28. pii: S1567-5769(25)01740-0. [Epub ahead of print]167 115752

Metabolomics reveals the immunomodulation of endophytic fungal exopolysaccharides from Cyclocarya paliurus in RAW264.7 macrophages via MAPK pathway and metabolic reprogramming.

Gang Wang, Xin Tao, Zhibing Huang, Yuanxing Wang, Jianhua Xie.

  Three endophytic fungal exopolysaccharides (EPSs) from Cyclocarya paliurus can enhance the proliferation of RAW264.7 and exhibit obvious immunomodulatory effects. The immunomodulatory mechanism information of endophytic fungal EPSs from Cyclocarya paliurus in RAW264.7 macrophages is still relatively lacking. This study explores how these EPSs affect RAW264.7 phagocytosis and the secretion of nitric oxide (NO), cytokines, and reactive oxygen species (ROS), and examines their metabolic reprogramming and immune-activation mechanisms in RAW264.7 cells via cell metabolomics. Results showed that all three EPSs enhance phagocytic activity and levels of NO, cytokines, and ROS in RAW264.7 cells, and induced M1 macrophage polarization via the mitogen-activated protein kinase (MAPK) pathway. Metabolomics reveals that Monascus purpureus exopolysaccharide (MPE) and Aspergillus versicolor exopolysaccharide (AVE) cause marked changes in energy, amino acid, and lipid metabolism. Penicillium citrinum exopolysaccharide (PCE) uniquely enhances immunity without lipid metabolism disruption or severe oxidative stress. Collectively, PCE emerged as a promising immunomodulator with a favorable risk-benefit profile in vitro. It effectively triggers immune responses, minimizing metabolic disruption and oxidative stress, which highlights its potential for developing immune regulators.

Keywords:  Exopolysaccharide; Immunological activity; Metabolomics; RAW264.7

DOI:  https://doi.org/10.1016/j.intimp.2025.115752
BMB Rep. 2025 Oct 31. pii: 6569. [Epub ahead of print]

Alloxan attenuates glucosamine-induced NF-κB activation and proinflammatory gene expression under normoglycemic conditions.

Sang-Min Kim, Chanhaeng Lee, Dong Yeol Kim, Inn-Oc Han.

Glucosamine (GlcN), a critical substrate in the hexosamine biosynthetic pathway, is known to modulate inflammatory responses in macrophages depending on extracellular glucose concentration. In hyperglycemic conditions (25 mM glucose), GlcN suppresses the production of nitric oxide (NO) and decreases the expression of inducible nitric oxide synthase (iNOS). Conversely, under normoglycemic conditions (5 mM glucose), GlcN paradoxically enhances lipopolysaccharide (LPS)-induced iNOS expression, NO production, and the upregulation of additional proinflammatory mediators. In this study, we examined the effect of alloxan, a known O-GlcNAc transferase (OGT) inhibitor, on GlcN- and/or LPS-mediated inflammatory responses in RAW264.7 macrophage cells. Under hyperglycemic conditions, alloxan exhibited little effect on the LPS-induced or LPS plus GlcN-induced expression of iNOS, cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). In contrast, under normoglycemic conditions, alloxan significantly inhibited the induction of these inflammatory genes in response to LPS plus GlcN. At the mechanistic level, alloxan reduced NF-κB DNA-binding activity and prevented its recruitment to the iNOS promoter. In addition, alloxan attenuated GlcN-induced increase in OGlcNAcylation of the NF-κB subunit p65. Collectively, these results indicate that OGT-mediated O-GlcNAcylation of NF-κB is critical for GlcN-induced proinflammatory signaling under normoglycemia. Our work highlights the glucose dependency of O-GlcNAc cycling in macrophage responses and provides new perspectives on the metabolic regulation of innate immune responses.
Circ Res. 2025 Oct 30.

YAP-Induced Glycolysis Drives Fibroinflammation and Disrupts Fibroblast Fidelity.

Chang-Ru Tsai, Lin Liu, Yi Zhao, Jong Kim, Paulo Czarnewski, Rich Li, Fansen Meng, Mingjie Zheng, Jeffrey Steimle, Xiaolei Zhao, Francisco Grisanti, Zheng Sun, Jun Wang, Md Abul Hassan Samee, Xiao Li, James F Martin.

   BACKGROUND: Separation of the pulmonic and systemic circulation is essential for terrestrial life, and mammals have evolved distinct cardiac chambers with specialized structures and functions. Transcriptomics profiling revealed cellular heterogeneity between heart chambers. However, the mechanisms underlying chamber-specific transcriptomic and metabolic differences-and their functional significance-remain poorly understood. The Hippo/YAP (yes-associated protein) pathway is a conserved signaling network that regulates diverse cellular processes. The Hippo kinases inhibit YAP in cardiac fibroblasts (CF) to restrict fibrosis and inflammation. Nonetheless, how YAP regulates the metabolic microenvironment during homeostasis and fibroinflammation remains unclear.
METHODS: We investigated YAP and glycolysis activity in the 4 cardiac chambers by scoring the expression of YAP target genes and glycolysis genes in human single-nucleus RNA sequencing data. To compare glucose uptake between the left and right atria, we measured isotope-labeled glucose uptake in isolated mouse atria. To study the role of YAP in CFs, we inactivated the Hippo kinases, Lats1 and Lats2, in mouse CFs and performed metabolic studies, snRNA-seq, single-nucleus assay for transposase-accessible chromatin with sequencing, and spatial transcriptomics.
RESULTS: Metabolic and sequencing approaches revealed that Hippo-deficient CFs activated glycolysis to promote fibroinflammation. Inhibition of glycolysis or lactate production suppressed Hippo-deficient CF-induced fibrosis. Elevated YAP activity disrupted fibroblast lineage fidelity by inducing an osteochondroprogenitor cell state. Blocking macrophage expansion pharmacologically reduced Hippo-deficient CF proliferation and fibrosis. Sequencing and functional studies showed that macrophages secreted IGF1 (insulin-like growth factor 1) to activate IGF1 signaling in Hippo-deficient CFs to increase cell proliferation and fibrosis.
CONCLUSIONS: We discovered that right atrial CFs are more glycolytic and have higher YAP activity than CFs in other heart chambers. YAP activation in CFs induces glycolysis to drive fibrosis. YAP disrupts fibroblast lineage fidelity, driving them to a SOX9 (SRY-box transcription factor 9)-expressing osteochondroprogenitor cell state. Mechanistically, YAP activates the secretion of CSF1 (colony-stimulating factor 1) to promote macrophage expansion. Blocking macrophage expansion reduces Hippo-deficient CF proliferation, osteochondroprogenitor differentiation, and fibrosis, revealing that macrophages signal reciprocally to regulate CF cell states. Genomic and functional studies revealed that the upregulated IGF1 receptor in Hippo-deficient CFs enables them to receive macrophage-secreted IGF1, thereby further enhancing CF proliferation and fibrosis.

Keywords:  fibroblast; fibrosis; glycolysis; inflammation; isotope

DOI:  https://doi.org/10.1161/CIRCRESAHA.125.326480