bims-imicid 2025-04-13 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2025–04–13
twenty-six papers selected by
Dylan Ryan, University of Cambridge

Mitochondrial fatty acid synthesis and MECR regulate CD4+ T cell function and oxidative metabolism.
HIF-1 regulates mitochondrial function in bone marrow-derived macrophages but not in tissue-resident alveolar macrophages.
Age- and diet-instructed metabolic rewiring of the tumor-immune microenvironment.
Asparagine transporter supports macrophage inflammation via histone phosphorylation.
NK cell-derived IFNγ mobilizes free fatty acids from adipose tissue to promote early B cell activation during viral infection.
Dynamic regulation of neutrophil immunometabolism by platelet-derived metabolites.
Succinate contributes to Staphylococcus aureus skin infection by reactive oxygen species-hypoxic inducible factor 1α-glycolysis axis.
Succinate-loaded tumor cell-derived microparticles reprogram tumor-associated macrophage metabolism.
Mitochondrial dynamics at the intersection of macrophage polarization and metabolism.
Polychlorinated biphenyls induce immunometabolic switch of antiinflammatory macrophages toward an inflammatory phenotype.
3β-hydroxysteroid-Δ24 reductase integrates cholesterol metabolism and innate immune to promote PRRSV replication.
BNIP3-mediated mitophagy in macrophages regulates obesity-induced adipose tissue metaflammation.
Roles of Circadian Clocks in Macrophage Metabolism: Implications in Inflammation, and Metabolism of Lipids, Glucose, and Amino Acids.
Cancer cell-derived arginine fuels polyamine biosynthesis in tumor-associated macrophages to promote immune evasion.
Lacc1-engineered extracellular vesicles reprogram mitochondrial metabolism to alleviate inflammation and cartilage degeneration in TMJ osteoarthritis.
PKM2-mediated metabolic reprogramming of microglia in neuroinflammation.
Mitochondrial fusion reduces T cell susceptibility to HIV infection through citrate modulation.
An effective approach to modulate mitochondrial function in murine primary macrophages by a mitochondria-targeted nanocapsule, MITO-Porter.
L-Arginine and Immune Modulation: A Pharmacological Perspective on Inflammation and Autoimmune Disorders.
Metabolic reprogramming in T cell senescence: a novel strategy for cancer immunotherapy.
SAM transmethylation pathway and adenosine recycling to ATP are essential for systemic regulation and immune response.
The PERK-ATF4 pathway is required for metabolic reprogramming and progressive lung fibrosis.
NAD+ boosting increases atherosclerotic plaques and inflammation in Apoe knockout mice.
Pyruvate kinase M2 activation reprograms mitochondria in CD8 T cells, enhancing effector functions and efficacy of anti-PD1 therapy.
Lactate activates trained immunity by fueling the tricarboxylic acid cycle and regulating histone lactylation.
Vps34-orchestrated lipid signaling processes regulate the transitional heterogeneity and functional adaptation of effector regulatory T cells.

J Immunol. 2025 Apr 09. pii: vkaf034. [Epub ahead of print]

Mitochondrial fatty acid synthesis and MECR regulate CD4+ T cell function and oxidative metabolism.

KayLee K Steiner, Arissa C Young, Andrew R Patterson, Ayaka Sugiura, McLane J Watson, Samuel E J Preston, Anton Zhelonkin, Erin Q Jennings, Channing Chi, Darren R Heintzman, Andrew P Pahnke, Yasmine T Toudji, Zaid Hatem, Matthew Z Madden, Emily N Arner, Allison E Sewell, Allison K Blount, Richmond Okparaugo, Emilia Fallman, Evan S Krystofiak, Ryan D Sheldon, Katherine N Gibson-Corley, Kelsey Voss, Sara M Nowinski, Russell G Jones, Denis A Mogilenko, Jeffrey C Rathmell.

  Imbalanced effector and regulatory CD4+ T cell subsets drive many inflammatory diseases. These T cell subsets rely on distinct metabolic programs, modulation of which differentially affects T cell fate and function. Lipid metabolism is fundamental yet remains poorly understood across CD4+ T cell subsets. Therefore, we performed targeted in vivo CRISPR/Cas9 screens to identify lipid metabolism genes and pathways essential for T cell functions. These screens established mitochondrial fatty acid synthesis genes Mecr, Mcat, and Oxsm as key metabolic regulators. Of these, the inborn error of metabolism gene Mecr was most dynamically regulated. Mecrfl/fl; Cd4cre mice had normal naïve CD4+ and CD8+ T cell numbers, demonstrating that MECR is not essential in homeostatic conditions. However, effector and memory T cells were reduced in Mecr knockout and MECR-deficient CD4+ T cells and proliferated, differentiated, and survived less well than control T cells. Interestingly, T cells ultimately showed signs of mitochondrial stress and dysfunction in the absence of MECR. Mecr-deficient T cells also had decreased mitochondrial respiration, reduced tricarboxylic acid intermediates, and accumulated intracellular iron, which appeared to contribute to increased cell death and sensitivity to ferroptosis. Importantly, MECR-deficient T cells exhibited fitness disadvantages and were less effective at driving disease in an in vivo model of inflammatory bowel disease. Thus, MECR-mediated metabolism broadly supports CD4+ T cell proliferation and survival in vivo. These findings may also provide insight to the immunological state of MECR- and other mitochondrial fatty acid synthesis-deficient patients.

Keywords:  CD4+ T cells; MECR; lipid metabolism; mtFAS

DOI:  https://doi.org/10.1093/jimmun/vkaf034
Sci Rep. 2025 Apr 04. 15(1): 11574

HIF-1 regulates mitochondrial function in bone marrow-derived macrophages but not in tissue-resident alveolar macrophages.

Parker S Woods, Rengül Cetin-Atalay, Angelo Y Meliton, Kaitlyn A Sun, Obada R Shamaa, Kun Woo D Shin, Yufeng Tian, Benjamin Haugen, Robert B Hamanaka, Gökhan M Mutlu.

  HIF-1α plays a critical role in shaping macrophage phenotype and effector function. We have previously shown that tissue-resident alveolar macrophages (TR-AMs) have extremely low glycolytic capacity at steady-state but can shift toward glycolysis under hypoxic conditions. Here, we generated mice with tamoxifen-inducible myeloid lineage cell specific deletion of Hif1a (Hif1afl/fl:LysM-CreERT2+/-) and from these mice, we isolated TR-AMs and bone marrow-derived macrophages (BMDMs) in which Hif1a is deleted. We show that TR-AM HIF-1α is required for the glycolytic shift under prolyl hydroxylase inhibition but is dispensable at steady-state for inflammatory effector function. In contrast, HIF-1α deletion in BMDMs led to diminished glycolytic capacity at steady-state and reduced inflammatory capacity, but higher mitochondrial function. Gene set enrichment analysis revealed enhanced c-Myc transcriptional activity in Hif1a-/- BMDMs, and upregulation of gene pathways related to ribosomal biogenesis and cellular proliferation. We conclude that HIF-1α regulates mitochondrial function in BMDMs but not in TR-AMs. The findings highlight the heterogeneity of HIF-1α function in distinct macrophage populations and provide new insight into how HIF-1α regulates gene expression, inflammation, and metabolism in different types of macrophages.

Keywords:  Alveolar macrophage; Bone marrow-derived macrophage; HIF-1α; Inflammation; Metabolism; Mitochondria

DOI:  https://doi.org/10.1038/s41598-025-95962-3
J Exp Med. 2025 Jun 02. pii: e20241102. [Epub ahead of print]222(6):

Age- and diet-instructed metabolic rewiring of the tumor-immune microenvironment.

Ana Belén Plata-Gómez, Ping-Chih Ho.

The tumor-immune microenvironment (TIME) plays a critical role in tumor development and metastasis, as it influences the evolution of tumor cells and fosters an immunosuppressive state by intervening the metabolic reprogramming of infiltrating immune cells. Aging and diet significantly impact the metabolic reprogramming of the TIME, contributing to cancer progression and immune evasion. With aging, immune cell function declines, leading to a proinflammatory state and metabolic alterations such as increased oxidative stress and mitochondrial dysfunction, which compromise antitumor immunity. Similarly, dietary factors, particularly high-fat and high-sugar diets, promote metabolic shifts, creating a permissive TIME by fostering tumor-supportive immune cell phenotypes while impairing the tumoricidal activity of immune cells. In contrast, dietary restrictions have been shown to restore immune function by modulating metabolism and enhancing antitumor immune responses. Here, we discuss the intricate interplay between aging, diet, and metabolic reprogramming in shaping the TIME, with a particular focus on T cells, and highlight therapeutic strategies targeting these pathways to empower antitumor immunity.

DOI: https://doi.org/10.1084/jem.20241102
Sci Adv. 2025 Apr 11. 11(15): eads3506

Asparagine transporter supports macrophage inflammation via histone phosphorylation.

Chuanlong Wang, Yuyi Ye, Muyang Zhao, Qingyi Chen, Bingnan Liu, Wenkai Ren.

Solute carrier (SLC) family is essential for immune responses; nevertheless, whether and how SLCs regulate macrophage inflammation remains unclear. Here, we demonstrate that K636 acetylation mediates high abundance of SLC6A14 in inflammatory macrophages. Notably, the pharmacological inhibition or genetic modulation of SLC6A14 reduces macrophage interleukin-1β (IL-1β) secretion dependently of lower asparagine uptake and subsequently enhanced nuclear LKB1. Mechanistically, nuclear LKB1 lessens MAPK pathway-mediated NLRP3 inflammasome activation by increased histone 3 S10/28 phosphorylation-dependent cyclin O transcription. Moreover, myeloid Slc6a14 deficiency alleviates pulmonary inflammation via suppressing inflammatory macrophage responses. Overall, these results uncover a network by which SLC6A14-mediated asparagine uptake orchestrates macrophage inflammation through histone phosphorylation, providing a crucial target for modulation of inflammatory diseases.

DOI: https://doi.org/10.1126/sciadv.ads3506
Nat Metab. 2025 Apr 11.

NK cell-derived IFNγ mobilizes free fatty acids from adipose tissue to promote early B cell activation during viral infection.

Mia Krapić, Inga Kavazović, Sanja Mikašinović, Karlo Mladenić, Fran Krstanović, Gönül Seyhan, Sabine Helmrath, Elena Camerini, Ilija Brizić, Fleur S Peters, Marc Schmidt-Supprian, Bojan Polić, Tamara Turk Wensveen, Felix M Wensveen.

The immune system plays a major role in the regulation of adipose tissue homeostasis. Viral infection often drives fat loss, but how and why this happens is unclear. Here, we show that visceral adipose tissue transiently decreases adiposity following viral infection. Upon pathogen encounter, adipose tissue upregulates surface expression of ligands for activating receptors on natural killer cells, which drives IFNγ secretion. This cytokine directly stimulates adipocytes to shift their balance from lipogenesis to lipolysis, which leads to release of lipids in circulation, most notably of free fatty acids. The free fatty acid oleic acid stimulates early-activated B cells by promoting oxidative phosphorylation. Oleic acid promoted expression of co-stimulatory B7 molecules on B cells and promoted their ability to prime CD8+ T cells. Inhibiting lipid uptake by activated B cells impaired CD8+ T cell responses, causing an increase of viral replication in vivo. Our findings uncover a previously unappreciated mechanism of metabolic adaptation to infection and provide a better understanding of the interactions between immune cells and adipose tissue in response to inflammation.

DOI: https://doi.org/10.1038/s42255-025-01273-2
Front Immunol. 2025 ;16 1542438

Dynamic regulation of neutrophil immunometabolism by platelet-derived metabolites.

Manuel Alejandro Mosso-Pani, Dante Barreda, Ma Isabel Salazar.

  Platelets, traditionally known for their roles in hemostasis and thrombosis, have emerged as key regulators of immune responses, particularly through their dynamic interactions with neutrophils. This review explores how platelets influence neutrophil functions by forming platelet-neutrophil aggregates, releasing extracellular vesicles, and secreting metabolites. These processes govern critical immune activities, including cell recruitment, activation, endothelium interactions and the resolution or exacerbation of inflammation. Additionally, platelets induce metabolic reprogramming in neutrophils, affecting glycolysis and mitochondrial pathways, while also shaping the immune microenvironment by modulating other immune cells, such as T and B cells. Understanding this complex crosstalk between platelets and neutrophils-two of the most abundant cell types in the bloodstream-might reveal new therapeutic opportunities to regulate immune responses in inflammatory and immune-mediated diseases.

Keywords:  inflammation regulation; mitochondrial metabolism; neutrophil immunometabolism; platelet-derived metabolites; platelet-neutrophil aggregates

DOI:  https://doi.org/10.3389/fimmu.2025.1542438
Microb Pathog. 2025 Apr 02. pii: S0882-4010(25)00254-2. [Epub ahead of print]204 107529

Succinate contributes to Staphylococcus aureus skin infection by reactive oxygen species-hypoxic inducible factor 1α-glycolysis axis.

Xing Gao, Min Yu, Tianfeng Huang, Yali Ge, Ju Gao.

  Skin and soft tissue infections (SSTIs) caused by Staphylococcus aureus (S. aureus), one of the most prevalent and refractory diseases in humans and animals, are potentially involved in the metabolic reprogramming of pathogens and hosts. This study identified succinate as a danger signal. Succinate elevates mitochondrial ROS (mROS) levels, leading to higher HIF1α expression and glycolysis. These changes ultimately drive inflammation. Moreover, as a metabolite shared by pathogens and hosts, succinate facilitated metabolic crosstalk during infection. Through the deletion of S. aureus sucD, our results demonstrated that succinate derived from S. aureus exacerbated infection-induced inflammation. Additionally, our observations revealed consistently high expression levels of S. aureus fumC, a downstream enzyme in succinate metabolism, during skin infection, which maintained elevated glycolysis levels through the depletion of fumarate in the infectious environment. Overall, our findings elucidated the mechanism by which succinate regulates glycolysis via the mROS-HIF1α axis and provided support for targeting bacterial metabolism as a mechanism to prevent bacterial metabolic reprogramming and the development of skin infection.

Keywords:  Glycolysis; Skin infection; Staphylococcus aureus; Succinate; mROS-HIF1α

DOI:  https://doi.org/10.1016/j.micpath.2025.107529
Sci Transl Med. 2025 Apr 09. 17(793): eadr4458

Succinate-loaded tumor cell-derived microparticles reprogram tumor-associated macrophage metabolism.

Shuya Lu, Jiexiao Li, Yonggang Li, Shichuan Liu, Yutong Liu, Yue Liang, Xifen Zheng, Yiyang Chen, Jinghui Deng, Huafeng Zhang, Jingwei Ma, Jiadi Lv, Yugang Wang, Bo Huang, Ke Tang.

The tumor microenvironment predominantly polarizes tumor-associated macrophages (TAMs) toward an M2-like phenotype, thereby inhibiting antitumor immune responses. This process is substantially affected by metabolic reprogramming; however, reeducating TAMs to enhance their antitumor capabilities through metabolic remodeling remains a challenge. Here, we show that tumor-derived microparticles loaded with succinate (SMPs) can remodel the metabolic state of TAMs. SMPs promote classical M1-like polarization of macrophages by enhancing glycolysis and attenuating the tricarboxylic acid (TCA) cycle in a protein succinylation-dependent manner. Mechanistically, succinate is delivered into the mitochondria and nucleus by SMPs, leading to succinylation of isocitrate dehydrogenase 2 (IDH2) and histone H3K122 within the lactate dehydrogenase A (Ldha) promoter region. Our findings provide a distinct approach for TAM polarization using cell membrane-derived microparticles loaded with endogenous metabolites, a platform that may be used more broadly for posttranslational modification-based tumor immunotherapy.

DOI: https://doi.org/10.1126/scitranslmed.adr4458
Front Immunol. 2025 ;16 1520814

Mitochondrial dynamics at the intersection of macrophage polarization and metabolism.

Pan Li, Zhengbo Fan, Yanlan Huang, Liang Luo, Xiaoyan Wu.

  Macrophages are vital sentinels in innate immunity, and their functions cannot be performed without internal metabolic reprogramming. Mitochondrial dynamics, especially mitochondrial fusion and fission, contributes to the maintenance of mitochondrial homeostasis. The link between mitochondrial dynamics and macrophages in the past has focused on the immune function of macrophages. We innovatively summarize and propose a link between mitochondrial dynamics and macrophage metabolism. Among them, fusion-related FAM73b, MTCH2, SLP-2 (Stomatin-like protein 2), and mtSIRT, and fission-related Fis1 and MTP18 may be the link between mitochondrial dynamics and macrophage metabolism association. Furthermore, post-translational modifications (PTMs) of mtSIRT play prominent roles in mitochondrial dynamics-macrophage metabolism connection, such as deacetylates and hypersuccinylation. MicroRNAs such as miR-150, miR-15b, and miR-125b are also possible entry points. The metabolic reprogramming of macrophages through the regulation of mitochondrial dynamics helps improve their adaptability and resistance to adverse environments and provides therapeutic possibilities for various diseases.

Keywords:  fission; fusion; macrophage; metabolism; mitochondrial dynamics

DOI:  https://doi.org/10.3389/fimmu.2025.1520814
PNAS Nexus. 2025 Apr;4(4): pgaf100

Polychlorinated biphenyls induce immunometabolic switch of antiinflammatory macrophages toward an inflammatory phenotype.

Riley M Behan-Bush, Michael V Schrodt, Elizabeth Kilburg, Jesse N Liszewski, Laura M Bitterlich, Karen English, Aloysius J Klingelhutz, James A Ankrum.

  Polychlorinated biphenyls (PCBs) are a group of environmental toxicants associated with increased risk of diabetes, obesity, and metabolic syndrome. These metabolic disorders are characterized by systemic and local inflammation within adipose tissue, the primary site of PCB accumulation. These inflammatory changes arise when resident adipose tissue macrophages undergo phenotypic plasticity-switching from an antiinflammatory to an inflammatory phenotype. Thus, we sought to assess whether PCB exposure drives macrophage phenotypic switching. We investigated how human monocyte-derived macrophages polarized toward an M1, M2a, or M2c phenotype were impacted by exposure to Aroclor 1254, a PCB mixture found at high levels in school air. We showed that PCB exposure not only exacerbates the inflammatory phenotype of M1 macrophages but also shifts both M2a and M2c cells toward a more inflammatory phototype in both a dose- and time-dependent manner. Additionally, we show that PCB exposure leads to significant metabolic changes. M2 macrophages exposed to PCBs exhibit increased reliance on aerobic glycolysis and reduced capacity for fatty acid and amino acid oxidation-both indicators of an inflammatory macrophage phenotype. Collectively, these results demonstrate that PCBs promote immunometabolic macrophage plasticity toward a more M1-like phenotype, thereby suggesting that PCBs exacerbate metabolic diseases by altering the inflammatory environment in adipose tissue.

Keywords:  PCBs; immunometabolism; plasticity; toxicology

DOI:  https://doi.org/10.1093/pnasnexus/pgaf100
Int J Biol Macromol. 2025 Apr 07. pii: S0141-8130(25)03419-1. [Epub ahead of print] 142867

3β-hydroxysteroid-Δ24 reductase integrates cholesterol metabolism and innate immune to promote PRRSV replication.

Yuchao Yan, Changyan Li, Qun Jie, Junyang Zhang, Yijia Liu, Yong Li, Daqing Cui, Depin Hua, Jinhai Huang.

  Cholesterol metabolism is a strategy used by PRRSV to inhibit host antiviral innate immunity. However, the key enzymes or the natural products and mechanisms involved have not been well elucidated. Here, we show that PRRSV infection upregulated DHCR24, the rate-limiting enzyme in the cholesterol synthesis pathway, to increase virus proliferation. We further elucidated that PRRSV Nsp4 interacts with the FAD domain of DHCR24, promoting its expression and increasing cellular cholesterol levels. In addition, U18666A treatment inhibited DHCR24 enzyme activity, significantly reduced cell cholesterol content and PRRSV replication, and exogenous cholesterol supplementation could rescued this effect. We also found that DHCR24 is a negative regulator of type I interferon (IFN-I) production upon viral infection. Mechanistically, DHCR24 interacts with TBK1 and disrupts the interaction of TBK1-IRF3, thereby inhibiting IRF3 phosphorylation and nuclear translocation. Taken together, these findings elucidate that DHCR24 is utilized by PRRSV to regulate host cholesterol content, inhibit the innate immune response, and promote virus proliferation.

Keywords:  Cholesterol metabolism; DHCR24; Innate immune; PRRSV

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.142867
Autophagy. 2025 Apr 07.

BNIP3-mediated mitophagy in macrophages regulates obesity-induced adipose tissue metaflammation.

Sangseob Kim, Cheoljun Choi, Yeonho Son, Junhyuck Lee, Sungug Joo, Yun-Hee Lee.

  Adipose tissue macrophages (ATMs) are key cellular components that respond to nutritional excess, contributing to obesity-induced inflammation and insulin resistance. However, the mechanisms underlying macrophage polarization and recruitment in adipose tissue during obesity remain unclear. In this study, we investigated mitophagy-dependent metabolic reprogramming in ATMs and identified a crucial role of the mitophagy receptor BNIP3 in regulating macrophage polarization in response to obesity. Mitophagic flux in ATMs increased following 12 weeks of high-fat diet (HFD) feeding, with Bnip3 levels upregulated in a HIF1A dependent manner, without affecting other mitophagy receptors. Macrophage-specific bnip3 knockout reduced HFD-induced adipose tissue inflammation and improved glucose tolerance and insulin sensitivity. Mechanistically, hypoxic conditions in vitro induced HIF1A-BNIP3-mediated mitophagy and glycolytic shift in macrophages. Furthermore, HIF1A-BNIP3 signaling-enhanced lipopolysaccharide-induced pro-inflammatory activation in macrophages. These findings demonstrate that BNIP3-mediated mitophagy regulates the glycolytic shift and pro-inflammatory polarization in macrophages and suggest that BNIP3 could be a therapeutical target for obesity-related metabolic diseases.

Keywords:  Adipose tissue macrophages; BNIP3; hypoxia; inflammation; metabolic diseases; mitophagy

DOI:  https://doi.org/10.1080/15548627.2025.2487035
Am J Physiol Endocrinol Metab. 2025 Apr 07.

Roles of Circadian Clocks in Macrophage Metabolism: Implications in Inflammation, and Metabolism of Lipids, Glucose, and Amino Acids.

Mohammad Irfan Dar, Yusuf Hussain, Xiaoyue Pan.

  Macrophages are essential immune cells that play crucial roles in inflammation and tissue homeostasis, and are important regulators of metabolic processes, such as the metabolism of glucose, lipids, and amino acids. The regulation of macrophage metabolism by circadian clock genes has been emphasized in many studies. Changes in metabolic profiles occurring after the perturbation of macrophage circadian cycles may underlie the etiology of several diseases. Specifically, chronic inflammatory disorders, such as atherosclerosis, diabetes, cardiovascular diseases, and liver dysfunction, are associated with poor macrophage metabolism. Developing treatment approaches that target metabolic and immunological ailments requires an understanding of the complex relationships among clock genes, disease etiology, and macrophage metabolism. This review explores the molecular mechanisms through which clock genes regulate lipid, amino acid, and glucose metabolism in macrophages, and discusses their potential roles in the development and progression of metabolic disorders. The findings underscore the importance of maintaining circadian homeostasis in macrophage function as a promising avenue for therapeutic intervention in diseases involving metabolic dysregulation, given its key roles in inflammation and tissue homeostasis. Moreover, reviewing the therapeutic implications of circadian rhythm in macrophages can help minimize the side effects of treatment. Novel strategies may be beneficial in treating immune-related diseases cause by shifted and blunted circadian rhythms via light exposure, jet lag, seasonal changes, and shift work or disruption to the internal clock (such as stress or disease).

Keywords:  Circadian clock; Glucose metabolism; Lipid metabolism; Macrophage; inflammation

DOI:  https://doi.org/10.1152/ajpendo.00009.2025
Cancer Cell. 2025 Apr 01. pii: S1535-6108(25)00116-3. [Epub ahead of print]

Cancer cell-derived arginine fuels polyamine biosynthesis in tumor-associated macrophages to promote immune evasion.

Yinghua Zhu, Ziwei Zhou, Xin Du, Xiaorong Lin, Zhi-Mei Liang, Si Chen, Yiwei Sun, Yue Wang, Zhenkun Na, Zhiyong Wu, Jiaxin Zhong, Beinan Han, Xiangping Zhu, Wenkui Fu, Hongde Li, Man-Li Luo, Hai Hu.

  Arginine metabolism reshapes the tumor microenvironment (TME) into a pro-tumor niche through complex metabolic cross-feeding among various cell types. However, the key intercellular metabolic communication that mediates the collective effects of arginine metabolism within the TME remains unclear. Here, we reveal that the metabolic interplay between cancer cells and macrophages plays a dominant role in arginine-driven breast cancer progression. Within the TME, breast cancer cells serve as the primary source of arginine, which induces a pro-tumor polarization of tumor-associated macrophages (TAMs), thereby suppressing the anti-tumor activity of CD8+ T cells. Notably, this cancer cell-macrophage interaction overrides the arginine-mediated enhancement of CD8+ T cell anti-tumor activity. Mechanistically, polyamines derived from arginine metabolism enhance pro-tumor TAM polarization via thymine DNA glycosylase (TDG)-mediated DNA demethylation, regulated by p53 signaling. Importantly, targeting the arginine-polyamine-TDG axis between cancer cells and macrophages significantly suppresses breast cancer growth, highlighting its therapeutic potential.

Keywords:  arginine; breast cancer; metabolic communication; polyamine; tumor microenvironment; tumor-associated macrophages

DOI:  https://doi.org/10.1016/j.ccell.2025.03.015
J Nanobiotechnology. 2025 Apr 05. 23(1): 276

Lacc1-engineered extracellular vesicles reprogram mitochondrial metabolism to alleviate inflammation and cartilage degeneration in TMJ osteoarthritis.

Xiaofeng Hu, Jian Xie, Jiansheng Su.

  Temporomandibular joint osteoarthritis (TMJOA) is a multifaceted degenerative disease characterized by progressive cartilage degradation, chronic pain, and functional limitations of the TMJ, significantly affecting patients' quality of life. Although metabolic homeostasis in chondrocytes is crucial for cartilage health, the mechanisms underlying metabolic dysregulation in TMJOA remain poorly characterized. This study aimed to investigate the metabolic imbalance in TMJOA cartilage and explore novel therapeutic strategies targeting metabolic reprogramming. RNA sequencing revealed a significant imbalance between glycolysis and oxidative phosphorylation (OXPHOS) in TMJOA cartilage, with a marked shift toward glycolysis, which is associated with inflammation and cartilage degradation. To counteract this imbalance, Laccase domain-containing 1 (Lacc1), a metabolic regulator involved in both inflammation and metabolic homeostasis, was selected for investigation, as its role in chondrocytes had not been explored. We engineered macrophage-derived extracellular vesicles (EVs) to overexpress Lacc1 (OE-EVs), aiming to restore metabolic balance and modulate inflammation in chondrocytes. In vitro, OE-EVs significantly reduced IL-1β-induced inflammation, inhibited glycolysis by decreasing key glycolytic enzymes, improved mitochondrial function by decreasing mitochondrial superoxide levels, and the restoration of normal mitochondrial structure. In vivo, micro-computed tomography (Micro-CT) and histological analyses demonstrated that OE-EVs effectively alleviated inflammation and promoted cartilage repair, as indicated by a 1.55-fold increase in toluidine blue-stained cartilage area compared to the TMJOA group, reflecting improved cartilage matrix integrity and proteoglycan retention. These findings highlight the therapeutic potential of Lacc1-engineered EVs to target mitochondrial metabolism, reestablish metabolic homeostasis, and reduce inflammation in TMJOA, offering a novel and promising strategy for improving clinical outcomes in TMJOA patients.

Keywords:  Chondrocytes; Engineered extracellular vesicles; Laccase domain-containing 1 (Lacc1); Mitochondrial metabolism; Temporomandibular joint osteoarthritis (TMJOA)

DOI:  https://doi.org/10.1186/s12951-025-03355-5
Cell Death Discov. 2025 Apr 06. 11(1): 149

PKM2-mediated metabolic reprogramming of microglia in neuroinflammation.

Qi Zhang, Sha-Sha Wang, Zhao Zhang, Shi-Feng Chu.

Microglia, the resident immune cells of the central nervous system, undergo metabolic reprogramming during neuroinflammation, playing a crucial role in the pathogenesis of neurological disorders such as Parkinson's disease. This review focuses on Pyruvate Kinase M2 (PKM2), a key glycolytic enzyme, and its impact on microglial metabolic reprogramming and subsequent neuroinflammation. We explore the regulatory mechanisms governing PKM2 activity, its influence on microglial activation and immune responses, and its contribution to the progression of various neurological diseases. Finally, we highlight the therapeutic potential of targeting PKM2 as a novel strategy for treating neuroinflammation-driven neurological disorders. This review provides insights into the molecular mechanisms of PKM2 in neuroinflammation, aiming to inform the development of future therapeutic interventions.

DOI: https://doi.org/10.1038/s41420-025-02453-5
J Leukoc Biol. 2025 Apr 11. pii: qiaf042. [Epub ahead of print]

Mitochondrial fusion reduces T cell susceptibility to HIV infection through citrate modulation.

Zichen Song, Jiangrong Wang, Zhihang Zheng, Zhixiang He, Jingna Xun, Ling Gu, Yinzhong Shen, Jun Chen.

  Inhibiting the metabolic activity of CD4+ T cells can effectively reduce HIV infection. Mitochondria, as critical organelles in eukaryotic metabolism, play a significant role in the progression of many diseases. The change of mitochondrial dynamics is an important process of mitochondrial regulation of cell metabolic activity. However, it remains uncertain whether regulating mitochondrial dynamics is a viable approach to reducing HIV infection. In this study, we demonstrated that promoting mitochondrial fusion in Jurkat cells through treatment with the mitochondrial fusion promoter M1 and the dynamin-related protein 1 (Drp1) inhibitor Mdivi1 conferred resistance to single-round VSVG-HIVNL4-3-GFP viral infection. Targeted metabolomics analysis revealed and subsequently confirmed the potential involvement of citrate in reducing HIV infection, which has been subsequently verified. And we found that plasma citrate level was negatively associated with HIV disease progression. Multi-omics results showed that citric acid leads to a decrease in the level of nucleotide metabolism in Jurkat cells. In conclusion, increased citrate levels resulting from mitochondrial fusion significantly impair the ability of HIV to infect cells, which may due to regulate nucleotide metabolism.

Keywords:  HIV; citrate; mitochondrial dynamic; nucleotide metabolism

DOI:  https://doi.org/10.1093/jleuko/qiaf042
Biomed Pharmacother. 2025 Apr 03. pii: S0753-3322(25)00213-6. [Epub ahead of print]186 118019

An effective approach to modulate mitochondrial function in murine primary macrophages by a mitochondria-targeted nanocapsule, MITO-Porter.

Mitsue Hibino, Tobia Filosi, Libia Lara Carrion, Emilio Porcu, Ankit Malhotra, Kerstin Lüdtke-Buzug, Saleh M Ibrahim, Yuma Yamada, Misa Hirose.

  Macrophages play crucial roles in various pathological conditions as well as maintenance of homeostasis. Many chronic inflammatory conditions, such as atherosclerosis, rheumatoid arthritis, and obesity, are known to involve the polarization of macrophages into a proinflammatory state. Therefore, controlling the function of macrophages is a potential strategy to intervene in such pathological conditions. Modulation of immune cell metabolism has recently received attention as a novel therapeutic strategy to counteract such conditions. Recently, a unique nanocapsule (MITO-Porter) that can deliver macromolecules specifically into mitochondria was generated, and its application to improve mitochondrial function was achieved by the direct action of the molecules at the site of the mitochondria in a wide range of cell types but not in immune cells. Therefore, we initiated this study by investigating the feasibility of mitochondria-targeted delivery of coenzyme Q10 (CoQ10), a known antioxidant and cofactor of mitochondrial oxidative phosphorylation, in primary murine bone marrow macrophages (BMDMs) and then evaluated the functional consequences of the treatment with MITO-Porter on mitochondrial function in BMDMs. At steady state, CoQ10-loaded MITO-Porter containing octaarginine (R8) was successfully delivered into the mitochondria, resulting in significant antioxidant effects and increased mitochondrial respiration. Furthermore, the effect of CoQ10 on mitochondrial function in BMDMs was more pronounced when CoQ10 was encapsulated in R8(+) MITO-Porter than when CoQ10 was added alone. This proof-of-concept study highlights the potential of the application of MITO-Porter in macrophages and other immune cells as a novel immunomodulatory therapy for chronic inflammatory conditions.

Keywords:  Bone-marrow-derived macrophages; Cell metabolism; Coenzyme Q10 (CoQ10); MITO-Porter; Macrophages; Mitochondria-targeted delivery

DOI:  https://doi.org/10.1016/j.biopha.2025.118019
Eur J Pharmacol. 2025 Apr 09. pii: S0014-2999(25)00369-3. [Epub ahead of print] 177615

L-Arginine and Immune Modulation: A Pharmacological Perspective on Inflammation and Autoimmune Disorders.

Igbayilola Yusuff Dimeji, Kasim Sakran Abass, Ngabea Murtala Audu, Adekola Saheed Ayodeji.

  L- Arginine (2-Amino-5-guanidinovaleric acid, L-Arg) is a semi-essential amino acid that is mainly produced within the urea cycle. It acts as a key precursor in the synthesis of proteins, urea, creatine, prolamines (including putrescine, spermine, and spermidine), proline, and nitric oxide (NO). WhenL-Arg is metabolized, it produces NO, glutamate, and prolamines, which all play important regulatory roles in various physiological functions. In addition to its metabolic roles,L-Arg significantly influences immune responses, especially in the context of inflammation and autoimmune diseases. It affects the activity of immune cells by modulating T-cell function, the polarization of macrophages, and the release of cytokines. Importantly,L-Arg plays a dual role in immune regulation, functioning as both an immunostimulatory and immunosuppressive agent depending on the specific cellular and biochemical environments. This review examines the immunopharmacological mechanisms of L-Arg, emphasizing its involvement in inflammatory responses and its potential therapeutic uses in autoimmune conditions like rheumatoid arthritis, multiple sclerosis, and inflammatory bowel disease. By influencing the pathways of nitric oxide synthase (NOS) and arginase (ARG), L-Arg helps maintain immune balance and contributes to the pathophysiology of diseases. Gaining a better understanding of the pharmacological effects of L-Arg on immune regulation could yield new perspectives on targeted treatments for immune-related diseases. Exploring its impact on immune signaling and metabolic pathways may result in novel therapeutic approaches for chronic inflammatory and autoimmune disorders.

Keywords:  L-Arginine; T-cell function; cytokine secretion; immune responses; inflammation; macrophage polarization; therapeutic applications

DOI:  https://doi.org/10.1016/j.ejphar.2025.177615
Cell Death Discov. 2025 Apr 09. 11(1): 161

Metabolic reprogramming in T cell senescence: a novel strategy for cancer immunotherapy.

Li Liu, Zhanying Hao, Xi Yang, Yan Li, Siyang Wang, Linze Li.

The complex interplay between cancer progression and immune senescence is critically influenced by metabolic reprogramming in T cells. As T cells age, especially within the tumor microenvironment, they undergo significant metabolic shifts that may hinder their proliferation and functionality. This manuscript reviews how metabolic alterations contribute to T cell senescence in cancer and discusses potential therapeutic strategies aimed at reversing these metabolic changes. We explore interventions such as mitochondrial enhancement, glycolytic inhibition, and lipid metabolism adjustments that could rejuvenate senescent T cells, potentially restoring their efficacy in tumor suppression. This review also focuses on the significance of metabolic interventions in T cells with aging and further explores the future direction of the metabolism-based cancer immunotherapy in senescent T cells.

DOI: https://doi.org/10.1038/s41420-025-02468-y
Elife. 2025 Apr 07. pii: RP105039. [Epub ahead of print]13

SAM transmethylation pathway and adenosine recycling to ATP are essential for systemic regulation and immune response.

Pavla Nedbalová, Nikola Kaislerova, Lenka Chodakova, Martin Moos, Tomáš Doležal.

  During parasitoid wasp infection, activated immune cells of Drosophila melanogaster larvae release adenosine to conserve nutrients for immune response. S-adenosylmethionine (SAM) is a methyl group donor for most methylations in the cell and is synthesized from methionine and ATP. After methylation, SAM is converted to S-adenosylhomocysteine, which is further metabolized to adenosine and homocysteine. Here, we show that the SAM transmethylation pathway is up-regulated during immune cell activation and that the adenosine produced by this pathway in immune cells acts as a systemic signal to delay Drosophila larval development and ensure sufficient nutrient supply to the immune system. We further show that the up-regulation of the SAM transmethylation pathway and the efficiency of the immune response also depend on the recycling of adenosine back to ATP by adenosine kinase and adenylate kinase. We therefore hypothesize that adenosine may act as a sensitive sensor of the balance between cell activity, represented by the sum of methylation events in the cell, and nutrient supply. If the supply of nutrients is insufficient for a given activity, adenosine may not be effectively recycled back into ATP and may be pushed out of the cell to serve as a signal to demand more nutrients.

Keywords:  D. melanogaster; S-adenosylhomocysteinase; SAM transmethylation pathway; adenosine kinase; adenosine signaling; adenylate kinase; biochemistry; chemical biology; immunology; inflammation; privileged immunity

DOI:  https://doi.org/10.7554/eLife.105039
JCI Insight. 2025 Apr 10. pii: e189330. [Epub ahead of print]

The PERK-ATF4 pathway is required for metabolic reprogramming and progressive lung fibrosis.

Jyotsana Pandey, Jennifer L Larson-Casey, Mallikarjun H Patil, Chao He, Nisarat Pinthong, A Brent Carter.

  Asbestosis is a prototypical type of fibrosis that is progressive and does not resolve. ER stress is increased in multiple cell types that contribute to fibrosis; however, the mechanism(s) by which ER stress in lung macrophages contributes to fibrosis is poorly understood. Here, we show that ER stress resulted in PERK activation in human subjects with asbestosis. Similar results were seen in asbestos-injured mice. Mice harboring a conditional deletion of Eif2ak3 were protected from fibrosis. Lung macrophages from asbestosis subjects had evidence of metabolic reprogramming to fatty acid oxidation (FAO). Eif2ak3fl/fl mice had increased oxygen consumption rate (OCR), whereas OCR in Eif2ak3-/-Lyz2-cre mice was reduced to control levels. PERK increased Atf4 expression, and ATF4 bound to the Ppargc1a promoter to increase its expression. GSK2656157, a PERK-specific inhibitor, reduced FAO, Ppargc1a, and Aft4 in lung macrophages and reversed established fibrosis in mice. These observations suggest that PERK is a unique therapeutic target to reverse established fibrosis.

Keywords:  Fatty acid oxidation; Fibrosis; Immunology; Macrophages; Pulmonology

DOI:  https://doi.org/10.1172/jci.insight.189330
Atherosclerosis. 2025 Apr 03. pii: S0021-9150(25)00086-3. [Epub ahead of print]404 119188

NAD+ boosting increases atherosclerotic plaques and inflammation in Apoe knockout mice.

Yu-Jen Wang, Daniel S Gaul, Era Gorica, Jürgen Pahla, Zeneng Wang, Shafeeq A Mohammed, Tina Dahlby, Elisa Dietrich, Elena Osto, Karim Gariani, Sarah Costantino, Stephan Winnik, Sokrates Stein, Stanley L Hazen, Frank Ruschitzka, Johan Auwerx, Christian M Matter.

   BACKGROUND AND AIMS: NAD+ (nicotinamide adenine dinucleotide) is a cosubstrate of the sirtuins (SIRT) that are activated upon caloric restriction. Supplementing NAD+ precursors such as nicotinamide riboside (NR) has been reported to extend life span and combat metabolic syndrome through pan-sirtuin activation in mice. Notably, sirtuins compete with poly (ADP-ribose) polymerase (PARP)1 and CD38 for NAD+. Supplementing NAD+ precursors did not improve cardiovascular outcome in the AIM-HIGH trial. Recently, the terminal NAD+ metabolite 4PY (N1-methyl-4-pyridone-3-carboxamide) was reported to increase inflammation and to be associated with cardiovascular risk. We aimed to investigate whether NR provides atheroprotection.
METHODS: 8-week-old male apolipoprotein E (Apoe) knockout mice were fed for 12 weeks a high-cholesterol diet supplemented with three NR doses: NR-, NR+, and NR++. RAW264.7 mouse macrophages and bone marrow macrophages were stimulated with oxLDL and NR.
RESULTS: NR++ enhanced plaque lesions in aortic sinus sections and increased plasma levels of TNFα, IL-6, and LDL-cholesterol. Liver and plasma NAD+ concentrations remained unchanged, but the downstream metabolite 4PY increased. In liver lysates, SIRT1 and lipoprotein receptors were decreased and CD38 increased in NR++; cleaved PARP1 and total PARylation decreased upon NR supplementation. In oxLDL-treated macrophages, high NR levels increased CD38 and CD86 expression.
CONCLUSIONS: High-dose NR supplementation in mice did not decrease but increase both aortic plaque lesions and systemic inflammation. These effects may be mediated by increased CD38 expression in macrophages, with NAD+ metabolism shifted from sirtuins towards CD38 and PARP1 pathways. Caution should be applied with presumed NAD+ boosters in patients with atherosclerosis.

Keywords:  Atherosclerosis; CD38; Liver; Macrophage; Nicotinamide adenine dinucleotide (NAD(+)); Nicotinamide riboside (NR)

DOI:  https://doi.org/10.1016/j.atherosclerosis.2025.119188
Cell Metab. 2025 Apr 02. pii: S1550-4131(25)00106-8. [Epub ahead of print]

Pyruvate kinase M2 activation reprograms mitochondria in CD8 T cells, enhancing effector functions and efficacy of anti-PD1 therapy.

Seyedeh Sahar Mortazavi Farsani, Jignesh Soni, Lu Jin, Anil Kumar Yadav, Shivani Bansal, Tian Mi, Leena Hilakivi-Clarke, Robert Clarke, Benjamin Youngblood, Amrita Cheema, Vivek Verma.

  Mitochondria regulate T cell functions and response to immunotherapy. We show that pyruvate kinase M2 (PKM2) activation enhances mitochondria-dependent effector functions in CD8 and chimeric antigen receptor (CAR)-T cells. Multi-omics and 13C-glucose tracer studies showed that PKM2 agonism alters one-carbon metabolism, decreasing methionine levels, resulting in hypomethylated nuclear and mitochondrial DNA and enhancing mitochondrial biogenesis and functions. PKM2 activation increased the recall responses and anti-tumor functions of CD8 T cells, enhancing adoptive cell therapy. In preclinical models, the PKM2 agonist induced CD8 T cell-dependent anti-tumor responses that synergized with anti-programmed death 1 (PD1) therapy. Immunologically, PKM2 agonists boosted the activation of effector T cells while reducing FoxP3+ T regulatory (Treg) cells in the tumors. The anti-PD1 combination enhanced the frequency of tumor-specific activated CD8 T cells. Together, PKM2 agonism increased mitochondrial functions supporting cell cytotoxicity. Hence, pharmacological targeting of PKM2 can be a clinically viable strategy for enhancement of adoptive cell therapy, in situ anti-tumor immune responses, and immune checkpoint blockade therapy. VIDEO ABSTRACT.

Keywords:  CD8 T cells; PD1 blockade; PKM2; adoptive cell therapy; immunotherapy; melanoma; metabolism; mitochondria

DOI:  https://doi.org/10.1016/j.cmet.2025.03.003
Nat Commun. 2025 Apr 04. 16(1): 3230

Lactate activates trained immunity by fueling the tricarboxylic acid cycle and regulating histone lactylation.

Huanhuan Cai, Xueyuan Chen, Yan Liu, Yingbo Chen, Gechang Zhong, Xiaoyu Chen, Shuo Rong, Hao Zeng, Lin Zhang, Zelong Li, Aihua Liao, Xiangtai Zeng, Wei Xiong, Cihang Guo, Yanfang Zhu, Ke-Qiong Deng, Hong Ren, Huan Yan, Zeng Cai, Ke Xu, Li Zhou, Zhibing Lu, Fubing Wang, Shi Liu.

Trained immunity refers to the long-term memory of the innate immune cells. However, little is known about how environmental nutrient availability influences trained immunity. This study finds that physiologic carbon sources impact glucose contribution to the tricarboxylic acid (TCA) cycle and enhance cytokine production of trained monocytes. Our experiments demonstrate that trained monocytes preferentially employe lactate over glucose as a TCA cycle substrate, and lactate metabolism is required for trained immune cell responses to bacterial and fungal infection. Except for the contribution to the TCA cycle, endogenous lactate or exogenous lactate also supports trained immunity by regulating histone lactylation. Further transcriptome analysis, ATAC-seq, and CUT&Tag-seq demonstrate that lactate enhance chromatin accessibility in a manner dependent histone lactylation. Inhibiting lactate-dependent metabolism by silencing lactate dehydrogenase A (LDHA) impairs both lactate fueled the TCA cycle and histone lactylation. These findings suggest that lactate is the hub of immunometabolic and epigenetic programs in trained immunity.

DOI: https://doi.org/10.1038/s41467-025-58563-2
PLoS Biol. 2025 Apr;23(4): e3003074

Vps34-orchestrated lipid signaling processes regulate the transitional heterogeneity and functional adaptation of effector regulatory T cells.

Erienne G Norton, Nicole M Chapman, Hao Shi, Xiaoxi Meng, Hongling Huang, Anil Kc, Sherri Rankin, Jordy Saravia, Sujing Yuan, Haoran Hu, Peter Vogel, Hongbo Chi.

Regulatory T cell (Treg) heterogeneity exists in lymphoid and non-lymphoid tissues, but we have limited understanding of context-dependent functions and spatiotemporal regulators of heterogenous Treg states, especially during perinatal life when immune tolerance is established. Here, we revealed that the class III PI3K Vps34 orchestrates effector Treg (eTreg) transitional heterogeneity during perinatal life. We found that loss of Vps34 reduced terminal eTreg accumulation in lymphoid tissues, associated with decreased Treg generation in non-lymphoid tissues and development of an early-onset autoimmune-like disease. After perinatal life, Vps34-deficient eTreg accumulation was further impaired due to reduced cell survival, highlighting temporal regulation of eTreg heterogeneity and maintenance by Vps34. Accordingly, inhibition of Vps34 in mature Tregs disrupted immune homeostasis but boosted anti-tumor immunity. Mechanistically, multiomics profiling approaches uncovered that Vps34-orchestrated transcriptional and epigenetic remodeling promotes terminal eTreg programming. Further, via genetic deletion of the Vps34-interacting proteins Atg14 or Uvrag in Tregs, we established that Atg14 but not Uvrag was required for the overall survival, but not terminal differentiation, of eTregs, suggesting that autophagy but not endocytosis partly contributed to Vps34-dependent effects. Accordingly, mice with Treg-specific loss of Atg14, but not Uvrag, had moderately disrupted immune homeostasis and reduced tumor growth, with Vps34- or Atg14-dependent gene signatures also being elevated in intratumoral Tregs from human cancer patients. Collectively, our study reveals distinct Vps34-orchestrated signaling events that regulate eTreg heterogeneity and functional adaptation and the pathophysiological consequences on autoimmunity versus anti-tumor immunity.

DOI: https://doi.org/10.1371/journal.pbio.3003074