bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2026–01–18
27 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. CDK3 drives neuron loss in Alzheimer's disease.
  2. GLP-1 receptor agonism counteracts omics aging in mice.
  3. Ageing rewires the body's tolerance to infection.
  4. Pore-forming venoms as a senolytic strategy.
  5. Enhanced crosstalk between α- and δ-cells promotes recurrent hypoglycaemia.
  6. Metformin inhibits nuclear egress of chromatin fragments in senescence and aging.
  7. Metabolic adaptation in CD4+ T cells promotes immunosuppression in sepsis.
  8. IRF4 sends alveolar macrophages spiraling into an identity crisis during type 2 immunity.
  9. A head start: Bone channels shape meningeal immunity.
  10. Nucleotide metabolic rewiring enables NLRP3 inflammasome hyperactivation in obesity.
  11. Metabolic adaptations rewire CD4+ T cells in a subset-specific manner in human critical illness with and without sepsis.
  12. Intelectin-2 is a broad-spectrum antimicrobial lectin.
  13. Hexokinase detachment from mitochondria drives the Warburg effect to support compartmentalized ATP production.
  14. Circulating metabolites, genetics and lifestyle factors in relation to future risk of type 2 diabetes.
  15. Endothelial FUNDC1 regulates metabolic reprogramming and the obesity-diabetes transition through the SIRT3/GATA2/endothelin-1 axis.
  16. Mitochondrial diseases.
  17. Excitatory amino acid transporters support mast cell degranulation via α-KG-mediated methylation of Spp1.
  18. To the nines: IL-9 boosts T cell function.
  19. An inflammatory and quiescent HSC subpopulation expands with age in humans.
  20. The metabolic mood: Cholesterol homeostasis as a convergence point for depression risk.
  21. Cholesterol-lowering effects of oats induced by microbially produced phenolic metabolites in metabolic syndrome: a randomized controlled trial.
  22. Tmem110 regulates the conformation of TRPML1 to maintain endolysosomal homeostasis and prevent mitochondrial DNA leakage and pathological self-DNA processing.
  23. 6-Phosphogluconate dehydrogenase promotes mitochondrial fusion and immune suppression in tumor-associated monocytic suppressor cells.
  24. Structural basis for late maturation steps of mitochondrial respiratory chain complex IV within the human respirasome.
  25. Intestinal epithelial TLR5 signaling promotes barrier-supportive macrophages.
  26. Human periportal liver assembloids.
  27. Single-cell exploration in natural language.
  1. Nat Aging. 2026 Jan 12.
    CDK3 drives neuron loss in Alzheimer's disease.
      
    DOI:  https://doi.org/10.1038/s43587-026-01065-7
  2. Nat Aging. 2026 Jan 15.
    GLP-1 receptor agonism counteracts omics aging in mice.
    Anna Kriebs.
      
    DOI:  https://doi.org/10.1038/s43587-025-01063-1
  3. Nature. 2026 Jan 14.
    Ageing rewires the body's tolerance to infection.
    Miguel P Soares, Elisa Jentho.
      
    Keywords:  Ageing; Cardiovascular biology; Diseases; Infection
    DOI:  https://doi.org/10.1038/d41586-025-04091-4
  4. Nat Aging. 2026 Jan 14.
    Pore-forming venoms as a senolytic strategy.
      
    DOI:  https://doi.org/10.1038/s43587-026-01070-w
  5. Nat Metab. 2026 Jan 13.
    Enhanced crosstalk between α- and δ-cells promotes recurrent hypoglycaemia.
      
    DOI:  https://doi.org/10.1038/s42255-025-01423-6
  6. Nat Aging. 2026 Jan 16.
    Metformin inhibits nuclear egress of chromatin fragments in senescence and aging.
    Takuya Kumazawa, Yanxin Xu, Yu Wang, Ji-Won Lee, Tara C O'Brien, Chia-Kang Ho, Murat Cetinbas, Aaron Weiner, Konrad Hochedlinger, Ruslan I Sadreyev, Nabeel Bardeesy, Chia-Wei Cheng, Bin He, Zhixun Dou.
      Chronic inflammation promotes aging and age-associated diseases. While metabolic interventions can modulate inflammation, how metabolism and inflammation are connected remains unclear. Cytoplasmic chromatin fragments (CCFs) drive chronic inflammation through the cGAS-STING pathway in senescence and aging. However, CCFs are larger than nuclear pores, and how they translocate from the nucleus to the cytoplasm remains uncharacterized. Here we report that chromatin fragments exit the nucleus via nuclear egress, a membrane trafficking process that shuttles large complexes across the nuclear envelope. Inactivating critical nuclear egress proteins, the ESCRT-III or Torsin complex, traps chromatin fragments at the nuclear membrane and suppresses cGAS-STING activation and senescence-associated inflammation. Glucose limitation or metformin inhibits CCF formation through AMPK-dependent phosphorylation and autophagic degradation of ALIX, an ESCRT-III component. In aged mice, metformin reduces ALIX, CCFs, and cGAS-mediated inflammation in the intestine. Our study identifies a mechanism linking metabolism and inflammation and suggests targeting the nuclear egress of chromatin fragments as a strategy to suppress age-associated inflammation.
    DOI:  https://doi.org/10.1038/s43587-025-01048-0
  7. Nat Immunol. 2026 Jan 15.
    Metabolic adaptation in CD4+ T cells promotes immunosuppression in sepsis.
    Nicole M Chapman, Hongbo Chi.
      
    DOI:  https://doi.org/10.1038/s41590-025-02403-4
  8. Immunity. 2026 Jan 13. pii: S1074-7613(25)00559-X. [Epub ahead of print]59(1): 5-7
    IRF4 sends alveolar macrophages spiraling into an identity crisis during type 2 immunity.
    Anika Hutton, Hernandez Moura Silva.
      A long-standing debate in the field asks whether resident tissue macrophages are terminally differentiated or remain capable of changing their fate and function during inflammation. In this issue of Immunity, Verwaerde et al. uncover an IRF4-driven circuit that reshapes alveolar macrophage identity and positions them as contributors to allergic pathophysiology.
    DOI:  https://doi.org/10.1016/j.immuni.2025.12.003
  9. Immunity. 2026 Jan 13. pii: S1074-7613(25)00560-6. [Epub ahead of print]59(1): 8-10
    A head start: Bone channels shape meningeal immunity.
    Jasmin Herz, Jonathan Kipnis.
      Immune cells from the skull marrow reach the meninges through bone channels. In this issue of Immunity, Eme-Scolan and colleagues show that these channels form neonatally and can be remodeled to alter immune access to the brain's borders. Their work suggests that the skull is a developmental checkpoint for neuroimmune defense, potentially shaping vulnerability or resilience across the lifespan.
    DOI:  https://doi.org/10.1016/j.immuni.2025.12.004
  10. Science. 2026 Jan 15. 391(6782): eadq9006
    Nucleotide metabolic rewiring enables NLRP3 inflammasome hyperactivation in obesity.
    Danhui Liu, Chuanli Zhou, Xiaochen Wang, Zhou Luo, Ruiyao Xu, Shanshan Huo, Lina Guo, Xuemei Luo, Shuhan Yang, Arielle Click, Janiece Vancil, Paola Barajas, Victor Mijares, Hamid Baniasadi, Nan Yan, Jan Rehwinkel, Dustin C Hancks, Elizabeth H Chen, Shuang Liang, Zhenyu Zhong.
      Obesity is a major disease risk factor due to obesity-associated hyperinflammation. We found that obesity induced Nod-like receptor pyrin domain-containing 3 (NLRP3) inflammasome hyperactivation and excessive interleukin (IL)-1β production in macrophages by disrupting SAM and HD domain-containing protein 1 (SAMHD1), a deoxynucleoside triphosphate (dNTP) hydrolase crucial for nucleotide balance. This caused aberrant accumulation of dNTPs, which can be transported into mitochondria, and initiated mitochondrial DNA (mtDNA) neosynthesis, which increased the presence of oxidized mtDNA and triggered NLRP3 hyperactivation. Deletion of SAMHD1 promoted NLRP3 hyperactivation in cells isolated from zebrafish, mice, and humans. SAMHD1-deficient mice showed elevated circulating IL-1β, insulin resistance, and metabolic dysfunction-associated steatohepatitis. Blocking dNTP mitochondrial transport prevented NLRP3 hyperactivation in macrophages from obese patients and SAMHD1-deficient mice. Our study revealed that obesity by inhibiting SAMHD1 rewired macrophage nucleotide metabolism, thereby triggering NLRP3 inflammasome hyperactivation to drive disease progression.
    DOI:  https://doi.org/10.1126/science.adq9006
  11. Nat Immunol. 2026 Jan 15.
    Metabolic adaptations rewire CD4+ T cells in a subset-specific manner in human critical illness with and without sepsis.
    Matthew T Stier, Allison E Sewell, Erin L Mwizerwa, Chooi Ying Sim, Samantha M Tanner, Casey M Nichols, Heather H Durai, Erin Q Jennings, Paul Lindau, Erin M Wilfong, Sarah N Obeidalla, V Eric Kerchberger, Dawn C Newcomb, Julie A Bastarache, Lorraine B Ware, Jeffrey C Rathmell.
      Metabolic and immunologic dysfunction, including pathological CD4+ T cell immunosuppression, are archetypal in critical illness, but whether these factors are mechanistically linked remains incompletely defined. Here we characterized the metabolic properties of human CD4+ T cells from critically ill patients with and without sepsis and healthy adults. CD4+ T cells in critical illness showed subset-specific metabolic plasticity, with regulatory T (Treg) cells preferentially acquiring glycolytic capacity that associated with sustained cellular fitness and worsened clinical illness. Adapted Treg cells were more metabolically flexible and stabilized suppressive markers FOXP3 and TIGIT under mitochondrial stress. Single-cell transcriptomics suggested reactive oxygen species (ROS) and kynurenine metabolism as drivers of Treg cell remodeling. Subsequent inhibition of ROS and kynurenine metabolism attenuated glycolytic adaptation and suppressive rewiring, respectively, in Treg cells. These findings indicate that metabolic dysfunction was a contributor to CD4+ T cell remodeling in critical illness and suggest avenues to restore effective immunity.
    DOI:  https://doi.org/10.1038/s41590-025-02390-6
  12. Nat Commun. 2026 Jan 13. 17(1): 231
    Intelectin-2 is a broad-spectrum antimicrobial lectin.
    Amanda E Dugan, Deepsing Syangtan, Eric B Nonnecke, Rajeev S Chorghade, Amanda L Peiffer, Jenny J Yao, Jessica Ille-Bunn, Dallis Sergio, Gleb Pishchany, Catherine Dhennezel, Hera Vlamakis, Sunhee Bae, Sheila Johnson, Chariesse Ellis, Soumi Ghosh, Jill W Alty, Carolyn E Barnes, Miri Krupkin, Gerardo Cárcamo-Oyarce, Katharina Ribbeck, Ramnik J Xavier, Charles L Bevins, Laura L Kiessling.
      Mammals regulate the localization, composition, and activity of their native microbiota at colonization sites. Lectins residing at these sites influence microbial populations, but their functional roles are often unclear. Intelectins are found in chordates at mucosal barriers, but their functions are not well characterized. In this study, we find that mouse intelectin-2 (mItln2) and human intelectin-2 (hItln2) engage and crosslink mucins via carbohydrate recognition. Moreover, both lectins recognize microbes within native microbial communities, including gram-positive and gram-negative isolates from the respiratory and gastrointestinal tracts. This ability to engage mammalian and microbial glycans arises from calcium-coordinated binding of carbohydrate residues within mucus and microbial surfaces. Microbes, but not human cells, bound by mItln2 or hItln2, suffer a loss of viability. These findings underscore the crucial antimicrobial role of mammalian intelectin-2 in mucosal defense, where it plays offensive (microbial killing) and defensive (mucus crosslinking) roles in regulating microbial colonization.
    DOI:  https://doi.org/10.1038/s41467-025-67099-4
  13. Nat Metab. 2026 Jan 16.
    Hexokinase detachment from mitochondria drives the Warburg effect to support compartmentalized ATP production.
    Kimberly S Huggler, Kyle M Flickinger, Matthew H Forsberg, Carlos A Mellado Fritz, Gavin R Chang, Meghan F McGuire, Christian M Capitini, Jason R Cantor.
      Hexokinase (HK) catalyses the phosphorylation of glucose to glucose 6-phosphate, marking the first step of glucose metabolism. Most cancer cells co-express two homologous HK isoforms, HK1 and HK2, which can each bind the outer mitochondrial membrane (OMM). CRISPR screens performed across hundreds of cancer cell lines indicate that both isoforms are dispensable for growth in conventional culture media. By contrast, HK2 deletion impaired cell growth in human plasma-like medium. Here we show that this conditional HK2 dependence can be traced to the subcellular distribution of HK1. Notably, OMM-detached (cytosolic) rather than OMM-docked HK supports cell growth and aerobic glycolysis (the Warburg effect), an enigmatic phenotype of most proliferating cells. We show that under conditions promoting increased translocation of HK1 to the OMM, HK2 is required for cytosolic HK activity to sustain this phenotype, thereby driving sufficient glycolytic ATP production. Our results reveal a basis for conditional HK2 essentiality and suggest that demand for compartmentalized ATP synthesis explains why cells engage in aerobic glycolysis.
    DOI:  https://doi.org/10.1038/s42255-025-01428-1
  14. Nat Med. 2026 Jan 14.
    Circulating metabolites, genetics and lifestyle factors in relation to future risk of type 2 diabetes.
    Jun Li, Jie Hu, Huan Yun, Zhendong Mei, Xingyan Wang, Kai Luo, Marta Guasch-Ferré, Xikun Han, Buu Truong, Jordi Merino, Chengyong Jia, Miguel Ruiz-Canela, Casey M Rebholz, Eun Hye Moon, Taryn Alkis, Guning Liu, Jie Yao, Xiyuan Zhang, Bianca C Porneala, Jordi Salas-Salvadó, Thomas J Wang, Josée Dupuis, Elizabeth Selvin, Xiuqing Guo, Shilpa N Bhupathiraju, Jennifer A Brody, Yongmei Liu, Alexis C Wood, Kari E North, Su Yon Jung, Ching-Ti Liu, Nona Sotoodehnia, Simin Liu, Lesley F Tinker, A Heather Eliassen, JoAnn E Manson, Jose C Florez, Robert E Gerszten, Clary B Clish, Liming Liang, Rozenn N Lemaitre, Katherine L Tucker, Stephen S Rich, Jerome I Rotter, Miguel Angel Martínez-González, Kathryn M Rexrode, James B Meigs, Eric Boerwinkle, Robert C Kaplan, Frank B Hu, Bing Yu, Qibin Qi.
      The human metabolome reflects complex metabolic states affected by genetic and environmental factors. However, metabolites associated with type 2 diabetes (T2D) risk and their determinants remain insufficiently characterized. Here we integrated blood metabolomic, genomic and lifestyle data from up to 23,634 initially T2D-free participants from ten cohorts. Of 469 metabolites examined, 235 were associated with incident T2D during up to 26 years of follow-up, including 67 associations not previously reported across bile acid, lipid, carnitine, urea cycle and arginine/proline, glycine and histidine pathways. Further genetic analyses linked these metabolites to signaling pathways and clinical traits central to T2D pathophysiology, including insulin resistance, glucose/insulin response, ectopic fat deposition, energy/lipid regulation and liver function. Lifestyle factors-particularly physical activity, obesity and diet-explained greater variations in T2D-associated versus non-associated metabolites, with specific metabolites revealed as potential mediators. Finally, a 44-metabolite signature improved T2D risk prediction beyond conventional factors. These findings provide a foundation for understanding T2D mechanisms and may inform precision prevention targeting specific metabolic pathways.
    DOI:  https://doi.org/10.1038/s41591-025-04105-8
  15. Nat Commun. 2026 Jan 16.
    Endothelial FUNDC1 regulates metabolic reprogramming and the obesity-diabetes transition through the SIRT3/GATA2/endothelin-1 axis.
    Jian Li, Dayong Li, Fujie Zhao, Yadong Wang, Hongmin Yao, Yin Wu, Junqing An, Zhixue Liu, Ye Ding, Ming-Hui Zou.
      Endothelial cell (EC) dysfunction is a hallmark of obesity and Type 2 diabetes mellitus (T2DM), yet the mechanisms linking vascular stress to systemic metabolic diseases remain unclear. Here, we investigated the role of the mitochondrial protein FUN14 domain-containing 1 (FUNDC1) in EC under nutritional overload. Using high-fat diet (HFD)-fed EC-specific Fundc1 knockout mice, human umbilical vein ECs, primary ECs, and vascular tissues from patients with obese/T2DM, we find that endothelial FUNDC1 expression is elevated under diabetic conditions, whereas its deletion protects mice from HFD-induced obesity, insulin resistance, and metabolic disorders. Mechanistically, overnutrition triggers nuclear export of the long isoform of SIRT3 (SIRT3-L) to mitochondria via FUNDC1, disinhibiting GATA2 and enhancing endothelin-1 (ET-1) production. Loss of FUNDC1 in ECs retains SIRT3-L in the nucleus, promoting GATA2 degradation and reducing ET-1. Endothelial FUNDC1 levels correlated positively with plasma ET-1 in individuals with obesity/T2DM. These findings identify endothelial FUNDC1 as a key regulator of vasculature-metabolic organ cross talks and obesity-diabetes transition.
    DOI:  https://doi.org/10.1038/s41467-026-68548-4
  16. Nat Biotechnol. 2026 Jan;44(1): 38
    Mitochondrial diseases.
      
    DOI:  https://doi.org/10.1038/s41587-025-02973-6
  17. Cell Mol Immunol. 2026 Jan 13.
    Excitatory amino acid transporters support mast cell degranulation via α-KG-mediated methylation of Spp1.
    Zhending Gan, Yaoyao Xia, Peng Bin, Muyang Zhao, Youyou Zhou, Bingnan Liu, Wenkai Ren.
      Excitatory amino acid transporters (EAATs) mediate the progression of inflammatory diseases. However, the involvement of EAATs in the activation of mast cells (MCs) and MC-associated diseases remains unclear. Here, we demonstrate that EAAT2 expression (encoded by Slc1a2) directed by immunoglobulin E (IgE)-mediated high-affinity IgE receptor (FcεRI)-p38 signaling is indispensable for MC degranulation through osteopontin (OPN, encoded by Spp1). Mechanistically, EAAT2 regulates intracellular glutamate/alpha-ketoglutarate/reactive oxygen species (ROS) metabolism to reduce the DNA and histone H3K9 methylation of Spp1. Most importantly, MC-specific depletion of Slc1a2 alleviates the allergic response in mice, and EAAT2 expression is positively correlated with MC-associated diseases in humans. Taken together, our findings establish a mechanistic link between amino acid transporters and epigenetic modifications with MC activation and provide potential therapeutic targets for allergic diseases.
    Keywords:  Excitatory amino acid transporter 2; Mast cell; Methylation; OPN; α-KG
    DOI:  https://doi.org/10.1038/s41423-025-01375-7
  18. Immunity. 2026 Jan 13. pii: S1074-7613(25)00562-X. [Epub ahead of print]59(1): 14-16
    To the nines: IL-9 boosts T cell function.
    Elizabeth Wickman, Maksim Mamonkin.
      IL-9 is canonically associated with anti-helminth and allergic immunity. However, in this issue of Immunity, Jiang et al. and Castelli et al. demonstrate how integrating IL-9 signaling in T cells enhances their persistence and anti-tumor function in solid cancer models.
    DOI:  https://doi.org/10.1016/j.immuni.2025.12.006
  19. Genome Biol. 2026 Jan 16.
    An inflammatory and quiescent HSC subpopulation expands with age in humans.
    Ksenia R Safina, Basit Salik, Dylan Kotliar, Michelle Curtis, Jonathan D Good, Chen Weng, Shawn David, Soumya Raychaudhuri, Antonia Kreso, Jennifer J Trowbridge, Vijay G Sankaran, Peter van Galen.
      Aging of the blood system impacts systemic health and can be traced to hematopoietic stem cells (HSCs). Despite multiple reports on human HSC aging, a unified map detailing their molecular age-related changes is lacking. We developed a consensus map of gene expression in HSCs by integrating seven single-cell datasets. This map reveals previously unappreciated heterogeneity within the HSC population. It also links inflammatory pathway activation (TNF/NFκB, AP-1) and quiescence within a single gene expression program. This program dominates an inflammatory HSC subpopulation that increases with age, highlighting a potential target for further experimental studies and anti-aging interventions.
    DOI:  https://doi.org/10.1186/s13059-026-03936-z
  20. Dev Cell. 2026 Jan 14. pii: S1534-5807(25)00769-5. [Epub ahead of print]61(1): 9-11
    The metabolic mood: Cholesterol homeostasis as a convergence point for depression risk.
    Mu Seog Choe, In-Hyun Park.
      Major depressive disorder arises from an interplay of genetic and environmental factors. In this issue of Developmental Cell, Oberst et al. reveal that chronic stress, inflammation, and SIRT1 deficiency converge on a defect in neuronal cholesterol homeostasis. Restoring cholesterol levels rescues this deficit, highlighting lipid metabolism as a driver of depression.
    DOI:  https://doi.org/10.1016/j.devcel.2025.12.008
  21. Nat Commun. 2026 Jan 14. 17(1): 598
    Cholesterol-lowering effects of oats induced by microbially produced phenolic metabolites in metabolic syndrome: a randomized controlled trial.
    Linda Klümpen, Aakash Mantri, Maren Philipps, Waldemar Seel, Laura Schlautmann, Mohamed H Yaghmour, Verena Wiemann, Birgit Stoffel-Wagner, Martin Coenen, Leonie Weinhold, Jan Hasenauer, Thomas Fließwasser, Sven Burgdorf, Christoph Thiele, Peter Stehle, Marie-Christine Simon.
      Oats have various positive effects on human health, but the underlying mechanisms are not fully understood. To identify oat-microbiome-host interactions contributing to metabolic improvements, we conducted two randomized controlled dietary interventions in parallel-design in individuals with metabolic syndrome, comparing a short-term, high-dose and a six-week, moderate oat intake with respective controls (DRKS00022169). Both oat diets lead to an increase in plasma ferulic acid (0.64 [0.26, 1.02], P = 0.002; 0.55 [0.21, 0.89], P = 0.003), while the high-dose oat-diet also increased dihydroferulic acid (1.23 [0.44, 2.01], P = 0.003). Here we show that microbial phenolic metabolites are driving factors for the cholesterol-lowering effect of oats, which might be of relevance since short-term, high-dose oat-diet is a suitable approach to alleviate obesity-related lipid disorders.
    DOI:  https://doi.org/10.1038/s41467-026-68303-9
  22. Nat Commun. 2026 Jan 15.
    Tmem110 regulates the conformation of TRPML1 to maintain endolysosomal homeostasis and prevent mitochondrial DNA leakage and pathological self-DNA processing.
    Zunyong Feng, Yuanbo Pan, Jing Zhou, Liuxi Chu, Qiang Li, Xuanbo Zhang, Ping Wu, Zhiliang Xu, Yanjiao Huang, Jianhua Zou, Xiaokun Li, Xiaoyuan Chen, Zhouguang Wang.
      The mechanisms by which phagocytes handle large quantities of internalized organelles, such as mitochondria released during tissue injury, remain unclear. Here we show that the endoplasmic reticulum transmembrane regulator TMEM110 is a key determinant of disease severity in traumatic brain injury-associated multiple organ dysfunction. Loss of TMEM110 impairs the clearance of mitochondria aberrantly released into the circulation, leading to heightened autoimmune-mediated tissue injury and mortality. TMEM110 maintains lysosomal function by controlling the conformational transition of the lysosomal ion channel TRPML1 and generating localized calcium efflux sites, thereby preventing calcium overload, membrane disruption, and leakage of mitochondrial DNA into the cytosol. We further find that TMEM110 expression is restrained by the nucleic acid sensor STING under basal conditions, and that a naturally occurring interface mutation between TMEM110 and STING causes defective lysosomal DNA disposal and aberrant type I interferon activity. These findings identify a feedback pathway linking cytosolic DNA sensing to organelle homeostasis.
    DOI:  https://doi.org/10.1038/s41467-026-68382-8
  23. Nat Commun. 2026 Jan 14. 17(1): 229
    6-Phosphogluconate dehydrogenase promotes mitochondrial fusion and immune suppression in tumor-associated monocytic suppressor cells.
    Saeed Daneshmandi, Qi Yan, Eduardo Cortes Gomez, Jee Eun Choi, Eriko Katsuta, Ehsan Gharib, Prashant K Singh, Richard M Higashi, Andrew N Lane, Teresa W-M Fan, Jianmin Wang, Elizabeth A Repasky, Philip L McCarthy, Hemn Mohammadpour.
      The mechanisms underlying the metabolic adaptation of myeloid cells within the tumor microenvironment remain incompletely understood. Here, we identify 6-phosphogluconate dehydrogenase (6PGD), a rate-limiting enzyme in the pentose phosphate pathway (PPP), as an important regulator of monocytic-myeloid derived suppressor cell (M-MDSC) function. Our findings reveal that tumor M-MDSCs upregulate 6PGD expression via IL-6/STAT3 signaling. Blocking 6PGD, using either genetic or pharmacological approaches, impairs the immunosuppressive function of M-MDSCs and suppresses tumor growth. Mechanistically, 6PGD inhibition leads to the accumulation of its substrate, 6-phosphogluconate (6PG), within M-MDSCs, activates the JNK1-IRS1 and PI3K-AKT-pDRP1 signaling pathways, leading to mitochondrial fragmentation and elevated mitochondrial reactive oxygen species (ROS). This metabolic shift drives M-MDSCs toward an M1-like proinflammatory phenotype. Furthermore, 6PGD blockade synergizes with anti-PD-1 immunotherapy in a preclinical tumor model, substantially improving therapeutic outcomes. Our data reveals 6PGD as a possible therapeutic target to disrupt M-MDSC function and improve cancer immunotherapy outcomes.
    DOI:  https://doi.org/10.1038/s41467-025-68102-8
  24. Nat Commun. 2026 Jan 10.
    Structural basis for late maturation steps of mitochondrial respiratory chain complex IV within the human respirasome.
    Minh Duc Nguyen, Ana Sierra-Magro, Vivek Singh, Anas Khawaja, Alba Timón-Gómez, Antoni Barrientos, Joanna Rorbach.
      The mitochondrial respiratory chain comprises four multimeric complexes (CI-CIV) that drive oxidative phosphorylation by transferring electrons to oxygen and generating the proton gradient required for ATP synthesis. These complexes can associate into supercomplexes (SCs), such as the CI + CIII₂ + CIV respirasome, but how SCs form, by joining preassembled complexes or by engaging partially assembled intermediates, remains unresolved. Here, we use cryo-electron microscopy to determine high-resolution structures of native human CI + CIII₂ + CIV late-assembly intermediates. Together with biochemical analyses, these structures show that respirasome biogenesis concludes with the final maturation of CIV while it is associated with fully assembled CI and CIII₂. We identify HIGD2A as a placeholder factor within isolated and supercomplexed CIV that is replaced by subunit NDUFA4 during the last step of CIV and respirasome assembly. This mechanism suggests that placeholders such as HIGD2A act as molecular timers, preventing premature incorporation of NDUFA4 or its isoforms and ensuring the orderly progression of pre-SC particles into functional respirasomes. Since defects in CIV assembly, including NDUFA4 deficiencies, cause severe encephalomyopathies and neurodegenerative disorders, understanding the molecular architecture and assembly pathways of isolated and supercomplexed CIV offers insight into the pathogenic mechanisms underlying these conditions.
    DOI:  https://doi.org/10.1038/s41467-025-68274-3
  25. Sci Immunol. 2026 Jan 23. 11(115): eadr4057
    Intestinal epithelial TLR5 signaling promotes barrier-supportive macrophages.
    Ming-Ting Tsai, Ryann Callaghan, Charles Ng, Lisette Peres-Tintin, Dean B Matthews, Nikketa Stanford, Karuna Ganesh, Mary K Estes, Gretchen E Diehl.
      Intestinal macrophages are essential for epithelial barrier repair. In homeostasis, macrophages are continuously replenished by recruitment of circulating C-C chemokine receptor 2 (CCR2)+ monocytes into the intestinal lamina propria (LP), a process that requires the commensal microbiota. The specific microbial factors and downstream host pathways that coordinate macrophage replenishment are inadequately understood. Here, we show that colonization with an Escherichia coli isolate increased CCR2+ macrophages in the intestine and ameliorated pathology in a colitis model. Using human colonic organoids, we report that E. coli colonization induced the secretion of C-C chemokine ligand 2 (CCL2) by intestinal epithelial stem cells, which promoted monocyte migration. Protection in vivo was abolished in the absence of epithelial CCL2. By screening a panel of E. coli, we identified that high flagellin expression correlated with epithelial CCL2 production. Demonstrating a requirement for E. coli flagellin, in vivo protection was lost in mice lacking epithelial Toll-like receptor 5 (TLR5) or after colonization with flagellin-deficient E. coli. Thus, epithelial flagellin sensing by TLR5 recruits CCR2+ macrophages to the intestine, promoting barrier repair.
    DOI:  https://doi.org/10.1126/sciimmunol.adr4057
  26. Nat Biotechnol. 2026 Jan;44(1): 39
    Human periportal liver assembloids.
    Iris Marchal.
      
    DOI:  https://doi.org/10.1038/s41587-025-02993-2
  27. Nat Methods. 2026 Jan;23(1): 10
    Single-cell exploration in natural language.
    Lin Tang.
      
    DOI:  https://doi.org/10.1038/s41592-025-03000-x
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