bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2026–07–19
thirty papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Mapping and manipulating aged and senescent microglia.
  2. Endocrine-like regulation through brown fat-secreted microRNAs.
  3. Restored clearance of senescent neutrophils by tissue-resident macrophages limits organ aging.
  4. Decoding MASLD progression beyond histological stages.
  5. The landscape of plasma proteomic links to human organ imaging.
  6. Trained immunity links hematopoietic stem cell aging to aging-associated inflammation.
  7. Spatio-DARLIN maps cell state and clonal history in intact mouse tissues.
  8. The transcription factor BACH1 couples chromatin priming and repression to enable macrophage plasticity and adaptation.
  9. Spatial mapping and senolytic targeting of senescent and disease-associated microglia in aged mouse brain white matter.
  10. The perineurium integrates leptin with its sympathetic outflow to protect against obesity.
  11. Good 4 u: A classic cytokine rejuvenates hematopoiesis.
  12. A transcriptional biosensor reveals mechanisms of α-ketoglutarate signaling to chromatin.
  13. Cholesterol-responsive NFE2L1-INSIG1 interaction controls VLDL secretion and metabolic dysfunction-associated steatohepatitis pathogenesis in mice.
  14. FDA Approves Hypertriglyceridemia Drug That May Reduce Pancreatitis Risk.
  15. Programming macrophage polarization with synthetic cytokine receptors.
  16. Reduced melanocortin tone modulates feeding during pregnancy in mice.
  17. An encyclopedia of human enhancer-gene regulatory interactions.
  18. SEC16B identified as a regulator of VLDL secretion and lipid accumulation in the liver.
  19. Anette Ziegler: breaking through boundaries in type 1 diabetes.
  20. Predicting Risk of Cognitive Impairment With Alzheimer Disease Blood Biomarkers.
  21. Integrated two-photon and photoacoustic microscopy for single-cell neurometabolic imaging.
  22. Macrophage-derived itaconate is a negative regulator of adipose tissue thermogenesis.
  23. Will making 'replication studies' easier to find help science self-correct?
  24. Macrophages are constitutive architects of tissue integrity.
  25. Targeting hepatic cholesterol sensing to tackle metabolic dysfunction-associated steatohepatitis.
  26. Cargo capture during ER-phagy.
  27. Itaconate as a paracrine brake on thermogenesis.
  28. Lymph nodes now optional.
  29. Lipid sensing and brain hormone receptors in food intake and glucose regulation.
  30. Internalized components of membrane attack complexes disrupt proteostasis and acquire alarmin-like properties.
  1. Nat Aging. 2026 Jul;6(7): 1360-1361
    Mapping and manipulating aged and senescent microglia.
      
    DOI:  https://doi.org/10.1038/s43587-026-01167-2
  2. Nat Metab. 2026 Jul 16.
    Endocrine-like regulation through brown fat-secreted microRNAs.
      
    DOI:  https://doi.org/10.1038/s42255-026-01570-4
  3. Science. 2026 Jul 16. 393(6808): eaea3075
    Restored clearance of senescent neutrophils by tissue-resident macrophages limits organ aging.
    Yuting Jessy Tan, Travis E Conley, Fuwen Yao, Fernando J García-Marqués, Damilola E Akinyemi, Van Vuong Dinh, Qian Wang, Abel Bermudez, Jieun Kim, Julia A Belk, Oliver Soehnlein, Sharon J Pitteri, Katrin I Andreasson.
      Aging disrupts tissue homeostasis across organ systems. Here, we identify tissue-resident macrophages (TRMs) as central coordinators of age-related organ decline through impaired clearance of senescent neutrophils, a process regulated by the immunomodulatory prostaglandin E2 (PGE2) receptor EP2. Reducing TRM EP2 signaling in aged mice preserved youthful mitochondrial fitness and prevented cognitive decline, frailty, sarcopenia, adiposity, cardiac impairment, and systemic inflammation. Plasma proteomics implicated the liver as a major source of age-associated immune change, in which reduced TRM EP2 signaling rescued neutrophil efferocytosis and prevented paracrine stress in neighboring cells. Elevated TRM EP2 expression and senescent neutrophils were also observed in aged and diseased human tissues. Pharmacologic EP2 inhibition restored youthful neutrophil clearance, establishing impaired TRM efferocytosis as a reversible driver of organ decline in aging.
    DOI:  https://doi.org/10.1126/science.aea3075
  4. Nat Metab. 2026 Jul 14.
    Decoding MASLD progression beyond histological stages.
      
    DOI:  https://doi.org/10.1038/s42255-026-01548-2
  5. Nat Commun. 2026 Jul 11.
    The landscape of plasma proteomic links to human organ imaging.
    Zirui Fan, Julio Chirinos, Xiaochen Yang, Juan Shu, Yujue Li, Joan M O'Brien, Walter Witschey, Daniel J Rader, Ruben Gur, Bingxin Zhao.
      Plasma protein levels provide important insights into human disease, yet a comprehensive assessment of plasma proteomics across organs is lacking. Using large-scale multimodal data from the UK Biobank, we integrate plasma proteomics with organ imaging to map their phenotypic and genetic links, analyzing 2923 proteins and 1051 imaging traits across multiple organs. We uncover 5067 phenotypic protein-imaging associations, identifying both organ-specific and organ-shared proteomic relations, along with enriched protein-protein interaction networks and biological pathways. Sensitivity analyses suggest that these associations are not substantially influenced by the median 10.18-year interval between plasma sampling and imaging visits. We also map key protein predictors of organ structures and show the stratification capability of plasma protein-based prediction models. Furthermore, we identify 8116 putative causal protein-imaging links. Imaging-associated protein components show enrichment across diverse complex diseases. Our study shows that integrating plasma proteomics with multi-organ imaging provides a comprehensive pan-organ imaging-proteomics map and reveals molecular pathways linking circulating proteins to human organ biology.
    DOI:  https://doi.org/10.1038/s41467-026-74715-4
  6. Nat Aging. 2026 Jul 16.
    Trained immunity links hematopoietic stem cell aging to aging-associated inflammation.
    Wei-Chieh Mu, Marine Barthez, Yufan Feng, Yibing Chen, Chih Ling Wang, Jing-Yi Huang, Jie Li, Paul Lanhart, Clair Tsui, Yang Joon Kim, Eric Verdin, Mihai G Netea, Danica Chen.
      Trained immunity is a state of heightened immune response that is initiated in hematopoietic stem cells (HSCs) and mediated mainly by their myeloid progeny. Aging-associated inflammation drives many aging-related diseases, yet its biological origin is largely unknown. Here we show that SIRT3, a mitochondrial deacetylase highly expressed in HSCs but reduced during aging, suppresses the HSC response to aging that drives maladaptive trained immunity, chronic inflammation and tissue functional decline in mice. Overexpression of SIRT3 in HSCs not only ameliorates aging-associated HSC decline, but also improves the function of distant tissues, including attenuation of age-related declines in cognition and motility, via myeloid cells with modulated inflammatory programs. These findings reveal that HSC aging is a driver of aging-associated inflammation through maladaptive trained immunity and broaden the possible clinical applications of targeting HSCs from hematological diseases to include countering aging-associated physiological decline and improving healthspan.
    DOI:  https://doi.org/10.1038/s43587-026-01175-2
  7. Nat Methods. 2026 Jul 17.
    Spatio-DARLIN maps cell state and clonal history in intact mouse tissues.
      
    DOI:  https://doi.org/10.1038/s41592-026-03157-z
  8. Immunity. 2026 Jul 17. pii: S1074-7613(26)00273-6. [Epub ahead of print]
    The transcription factor BACH1 couples chromatin priming and repression to enable macrophage plasticity and adaptation.
    Petros Tzerpos, Dóra Bojcsuk, Krisztian Bene, Noemí Caballero-Sánchez, Zofia Parteka-Tojek, Krzysztof Banecki, Sevastianos Korsak, Sarah M Pritchett, Andreas Patsalos, Darby Oleksak, Wilhelm K Berger, Michalis E Sarris, Nikolaos Giannakis, Sophie Chantalat, Timea Cseh, Evangelia K Papachristou, Ferenc Erdélyi, Zoltán Máté, Gabor Szabo, Gergely Nagy, Jason S Carroll, Charalampos G Spilianakis, John W R Schwabe, Dariusz Plewczynski, Laszlo Nagy.
      Macrophage activation and tissue adaptation involve precise transcriptional control by lineage-determining transcription factors (LDTFs) and stimulus-dependent TFs. The heme-regulated transcriptional repressor BACH1 clusters with myeloid LDTFs in unstimulated macrophages, suggesting a role in shaping macrophage identity and function. We found that BACH1 bound to both inactive and active regulatory regions, including latent enhancers. BACH1 recruited the NuRD complex and had dual functions, establishing early chromatin accessibility while actively repressing transcription. Upon inflammatory stimulation, BACH1 rapidly redistributed in cis to nearby promoters, reshaping chromatin occupancy, motif specificity, and enhancer-promoter interactions. BACH1 constrained 3D chromatin architecture, limiting enhancer mobility and TF complex dynamics. In vivo, Bach1 deletion impaired macrophage polarization and tissue adaptation and limited resilience during systemic and regenerative inflammation. Thus, BACH1 acts as an early chromatin accessibility-priming factor while actively repressing transcription-a regulatory activity that can be defined as pioneer repression-thereby shaping the macrophage epigenome in response to inflammatory and tissue contexts.
    Keywords:  BACH1; NuRD; adaptation; chromatin accessibility; enhancers; macrophages; pioneer repressor; plasticity; repression
    DOI:  https://doi.org/10.1016/j.immuni.2026.06.022
  9. Nat Aging. 2026 Jul;6(7): 1417-1436
    Spatial mapping and senolytic targeting of senescent and disease-associated microglia in aged mouse brain white matter.
    Chase M Carver, Paul T Gomez, Sonia L Rodriguez, James T Redden, Amanda S Latham, Yooree Ha, Jennifer M Kachergus, Yi Liu, Ji Shi, Tommy Tran, Liguo Wang, Simon Melov, E A Thompson, Marissa J Schafer.
      Brain white matter undergoes structural and functional alterations linked to late-life cognitive decline, but the cellular and molecular basis of its selective vulnerability remains incompletely defined. Here, in naturally aged mice, we demonstrate that senescent and disease-associated microglia (DAM) phenotypes converge in hippocampal-adjacent white matter, particularly in the fimbria. Using regional gene expression profiling, immunolabeling, GeoMx digital spatial profiling and CosMx spatial molecular imaging, we identify an aged brain-exclusive microglial population concentrated in white matter that expresses DAM genes together with a 'SenBrain' senescence gene signature, including galectin-3 (GAL3/Lgals3). Single-cell spatial trajectory analyses suggest that multiple cell fate transitions may give rise to this aged, proinflammatory, senescent- and DAM-linked state. Pharmacogenetic or pharmacological senotherapeutic interventions reduced white matter GAL3+ DAM abundance and restored a more youthful microglial organization in aged fimbria. These findings identify a senescence- and DAM-enriched microglial state as a prominent and partially reversible feature of aged brain white matter.
    DOI:  https://doi.org/10.1038/s43587-026-01154-7
  10. Nat Metab. 2026 Jul 13.
    The perineurium integrates leptin with its sympathetic outflow to protect against obesity.
    Gitalee Sarker, Emma Haberman, Anandhakumar Chandran, Thomas Monfeuga, Cyrielle Maroteau, Sofia Lundh, David S Oliveira, Andrea Raimondi, Karin Ziegler, Tiago Gomes, Tiago N Cordeiro, Karishma Parekh, Emilia Schmid, Paola Fernández-Sanmartín, Alina Griebel, Noelia Martinez-Sanchez, Bernardo A Arús, Samson W Cheung, Yitao Zhu, Michal Shaked, Sarah C L Knowles, Stefan Hanns Engelhardt, Matteo Iannacone, Philipp E Scherer, Miguel López, Enrique M Toledo, Ana Domingos.
      The regulatory mechanism of leptin's afferent action in the brain is contingent upon the efferent sympathetic innervation of white and brown adipose tissues. Nonetheless, the peripheral regulation governing the afferent-efferent balance remains ambiguous. Here we show the enriched expression of both leptin receptor (Lepr) and β2-adrenergic receptor (Adrb2) in perineurial cells that form a barrier around sympathetic ganglia and nerve bundles in adipose tissues, using single-cell RNA sequencing on mouse sympathetic ganglia. Lepr+ sympathetic perineurial cells (SPCs) are molecularly similar to endothelial cells. Conditional knockout of Adrb2 in Lepr+ cells, including SPCs, predisposes male mice to obesity by lowering energy expenditure and thermogenesis without affecting food intake. Notably, obesity-associated hyperleptinaemia causes apoptosis in SPCs, disrupting the perineurial barrier and concomitant adipose sympathetic neuropathy. This deleterious effect can be reversed by partial reduction of leptin or sympathomimetic β2-adrenergic receptor agonism. Clinically, we observed a male-specific synergistic effect of LEPR and ADRB2 polymorphisms on increased body mass index risk in a large European population. We propose that SPCs coordinate the afferent and efferent arms of the neuroendocrine loop of leptin action to regulate energy expenditure and body weight.
    DOI:  https://doi.org/10.1038/s42255-026-01555-3
  11. Immunity. 2026 Jul 14. pii: S1074-7613(26)00265-7. [Epub ahead of print]59(7): 1779-1781
    Good 4 u: A classic cytokine rejuvenates hematopoiesis.
    Kira L Florczak, Steven J Van Dyken.
      Aging and chronic inflammation alter hematopoiesis, impacting the hematopoietic progenitor populations in the bone marrow. In this issue of Immunity, Yao et al. show that the canonical type 2 cytokine interleukin 4 reverses age-related hematopoietic and physiologic effects by rebalancing progenitor fates.
    DOI:  https://doi.org/10.1016/j.immuni.2026.06.014
  12. Science. 2026 Jul 16. 393(6808): eadx8675
    A transcriptional biosensor reveals mechanisms of α-ketoglutarate signaling to chromatin.
    Alex C Sternisha, Haocheng Li, Kumar Gajendra, Yi Xiao, Xin Zhao, Jeffrey I Traylor, Lei Guo, Ji Hyung Jun, Morgan Fleishman, Tracey Shipman, Vinesh T Puliyappadamba, Pranita Kaphle, Qing Ouyang, Michael Schmidt, Diana D Shi, Milan R Savani, Alexander C-Y Tsai, Joyce H Lee, Ruth Gordillo, Javier Garcia-Bermudez, Yoon Jung Kim, Shih-Chia Tso, Chad A Brautigam, Lauren G Zacharias, Thomas P Mathews, Lin Xu, John G Doench, Vidyasagar Koduri, Kalil G Abdullah, Michalis Agathocleous, Laura A Banaszynski, Ralph J DeBerardinis, Eric M Morrow, Samuel K McBrayer.
      The metabolite α-ketoglutarate (αKG) is required for chromatin demethylation, but mechanisms that control αKG abundance in the nucleus are poorly defined. We designed a biosensor to monitor this metabolite pool in human cells using an αKG-responsive cyanobacterial transcription factor, NtcA, and used it to identify genes that regulate αKG in the nucleus. We defined an interorganelle pathway in which sequential mitochondrial activities of glutamic-pyruvic transaminase 2 (GPT2) and the SLC25A11 transporter supply nuclear αKG. In a mouse model of GPT2 deficiency, an inborn error of metabolism, Gpt2 loss caused histone hypermethylation in the brain and dysregulated neurodevelopmental genes. Restoring αKG counteracted these changes and promoted mouse fitness. Our work provides a tool to directly monitor nuclear αKG and reveals nuclear αKG depletion as a key pathogenic mechanism underlying GPT2 deficiency.
    DOI:  https://doi.org/10.1126/science.adx8675
  13. J Clin Invest. 2026 Jul 15. pii: e197094. [Epub ahead of print]136(14):
    Cholesterol-responsive NFE2L1-INSIG1 interaction controls VLDL secretion and metabolic dysfunction-associated steatohepatitis pathogenesis in mice.
    Shijun Deng, Jessica E Freed, Grace Y Lee, Gizel Askin, Zhe Cao, Özgür Cakici, Bo Yuan, Sheng Tony Hui, Karen E Inouye, Isabel Graupera, Gökhan S Hotamışlıgil.
      Cholesterol overload contributes to metabolic dysfunction-associated steatohepatitis (MASH) progression. One major pathway that limits hepatic cholesterol accumulation is export via VLDL secretion. While sterol regulatory element-binding protein (SREBP) activity is suppressed by insulin-induced gene 1 (INSIG1) under high sterol conditions, VLDL secretion nonetheless persists to prevent lipotoxicity and liver injury, presenting an unresolved paradox in cholesterol sensing and lipoprotein export. Here, we identified a cholesterol-responsive interaction between nuclear factor erythroid 2 related factor-1 (NFE2L1) and INSIG1 that preserved cholesterol homeostasis by sustaining VLDL secretion. Liver-specific NFE2L1 deletion elevated INSIG1 abundance, suppressed SREBP1 activation, and impaired VLDL secretion, leading to hepatic cholesterol accumulation and liver injury. Mechanistically, NFE2L1 bound to INSIG1 via its N-terminal homology box 2 (NHB2) domain; free cholesterol strengthened this interaction to promote INSIG1 degradation, thereby enabling SREBP1 activation and VLDL export. In NFE2L1-deficient mice, WT NFE2L1, but not a mutant NFE2L1 form unable to interact with INSIG1 (NHB2-deleted mutant, ΔNHB2), restored SREBP1 activity and VLDL secretion. Lipidomics analysis revealed that NFE2L1 deficiency reduced serum triglyceride composition, which was restored exclusively by WT NFE2L1. In a murine MASH model, NFE2L1 overexpression activated SREBP1/2, lowered hepatic cholesterol, and attenuated liver injury, inflammation, and fibrosis, without elevating atherogenic lipoproteins owing to compensatory LDL receptor upregulation. Together, these findings explain how VLDL secretion capacity was maintained under cholesterol excess and identify the NFE2L1/INSIG1 axis as a sterol-responsive safeguard for hepatic lipid homeostasis and a potential therapeutic target for MASH.
    Keywords:  Cholesterol; Hepatology; Inflammation; Lipidomics; Lipoproteins; Metabolism
    DOI:  https://doi.org/10.1172/JCI197094
  14. JAMA. 2026 Jul 17.
    FDA Approves Hypertriglyceridemia Drug That May Reduce Pancreatitis Risk.
    Samantha Anderer.
      
    DOI:  https://doi.org/10.1001/jama.2026.9480
  15. Nat Rev Immunol. 2026 Jul 14.
    Programming macrophage polarization with synthetic cytokine receptors.
    Tomislav Kostevc, Birgit Sawitzki.
      
    DOI:  https://doi.org/10.1038/s41577-026-01338-7
  16. Nat Commun. 2026 Jul 17.
    Reduced melanocortin tone modulates feeding during pregnancy in mice.
    Ingrid Camila Possa-Paranhos, Kerem Catalbas, Samuel Congdon, Dajin Cho, Tanya Pattnaik, Christina Nelson, Aarav Pathak, Vraj Patel, Patrick Sweeney.
      During pregnancy mammals increase their food intake to accommodate the elevated metabolic demands associated with fetal growth and development. However, the molecular and neural circuit mechanisms mediating increased feeding during pregnancy are largely unknown. Here, we demonstrate that arcuate nucleus agouti-related peptide (AgRP) neurons are activated and pro-opiomelanocortin (POMC) neurons are inhibited during pregnancy in mice. These changes are acutely required for promoting hyperphagia during pregnancy as chemogenetic inhibition of AgRP neurons or activation of POMC neurons both reduced the feeding of pregnant mice to non-pregnant levels. Finally, we utilized single cell resolution spatial transcriptomics in the arcuate nucleus of non-pregnant and pregnant mice to characterize pregnancy-induced changes in the transcriptomic state of arcuate nucleus neurons, including significant changes in many neurons controlling energy homeostasis, including AgRP and POMC neurons. Together, these findings outline a circuit mechanism regulating increased feeding during pregnancy, providing important mechanistic insights related to conditions at the intersection of reproduction and metabolism.
    DOI:  https://doi.org/10.1038/s41467-026-75650-0
  17. Nature. 2026 Jul 15.
    An encyclopedia of human enhancer-gene regulatory interactions.
    Andreas R Gschwind, Kristy S Mualim, Alireza Karbalayghareh, Maya U Sheth, Kushal K Dey, Evelyn Jagoda, Ramil N Nurtdinov, Wang Xi, Anthony S Tan, James Galante, Hank Jones, X Rosa Ma, David Yao, Dulguun Amgalan, Judhajeet Ray, Chad J Munger, Joseph Nasser, Žiga Avsec, Benjamin T James, Muhammad S Shamim, Neva C Durand, Suhas S P Rao, Ragini Mahajan, Benjamin R Doughty, Kalina Andreeva, Jacob C Ulirsch, Kaili Fan, Elizabeth M Perez, Tri C Nguyen, David R Kelley, Hilary K Finucane, Jill E Moore, Zhiping Weng, Manolis Kellis, Michael C Bassik, Berk Ustun, Alkes L Price, Michael A Beer, Roderic Guigó, John A Stamatoyannopoulos, Erez Lieberman Aiden, William J Greenleaf, Christina S Leslie, Lars M Steinmetz, Anshul Kundaje, Jesse M Engreitz.
      Identifying transcriptional enhancers and their target genes is essential for understanding gene regulation and the effect of human genetic variation on disease1-6. Here we create and evaluate a resource of more than 92 million enhancer-gene regulatory interactions across 1,458 biosamples covering 369 cell types and tissues, by integrating predictive models, chromatin states, three-dimensional contacts and large-scale genetic perturbations generated by the ENCODE Consortium7. We first create a systematic benchmarking pipeline to compare predictive models, assembling a dataset of 10,356 element-gene pairs measured in CRISPR perturbation experiments, more than 30,000 fine-mapped expression quantitative trait loci and 569 fine-mapped genome-wide association study (GWAS) variants linked to a probable causal gene. Using this framework, we develop ENCODE-rE2G, a predictive model achieving state-of-the-art performance across several prediction tasks, demonstrating that iterative perturbations and supervised machine learning can build increasingly accurate predictive models of enhancer regulation. Using ENCODE-rE2G, we build an encyclopedia of enhancer-gene regulatory interactions in the human genome, revealing global properties of enhancer networks, identifying differences in regulatory complexity across genes and improving analyses linking noncoding variants to target genes and cell types for common complex diseases. By interpreting the model, we find that beyond enhancer activity and three-dimensional enhancer-promoter contacts, additional features that guide enhancer-promoter communication include promoter class and enhancer-enhancer synergy. These genome-wide maps of enhancer-gene regulatory interactions, benchmarking software, predictive models and insights about enhancer function provide a valuable resource for future studies of gene regulation and human genetics.
    DOI:  https://doi.org/10.1038/s41586-026-10781-4
  18. J Clin Invest. 2026 Jul 15. pii: e208521. [Epub ahead of print]136(14):
    SEC16B identified as a regulator of VLDL secretion and lipid accumulation in the liver.
    Hossein Ardehali.
      The liver plays a major role in regulating the metabolic fate of lipids and facilitates lipid secretion to peripheral organs in the form of VLDLs or lipid storage in lipid droplets (LDs). Hepatic regulation of excess lipids profoundly influences the development of atherosclerosis; thus, uncovering the regulatory mechanisms underlying lipid storage and secretion pathways may reveal additional therapeutic targets. In this issue of the JCI, Lu et al. identified a pathway involving SEC16B, showing that this protein functions as a lipid-responsive regulator and mediates VLDL secretion and LD formation to maintain lipid homeostasis. They also demonstrated that a reduction in SEC16B reduced serum lipid levels and atherosclerotic plaque area in Ldlr-/- mice. These results indicate that SEC16B connects VLDL and LD metabolism, positioning SEC16B as a potential therapeutic avenue for atherosclerosis.
    DOI:  https://doi.org/10.1172/JCI208521
  19. Lancet. 2026 Jul 18. pii: S0140-6736(26)01387-5. [Epub ahead of print]408(10551): 205
    Anette Ziegler: breaking through boundaries in type 1 diabetes.
    Tony Kirby.
      
    DOI:  https://doi.org/10.1016/S0140-6736(26)01387-5
  20. JAMA. 2026 Jul 14.
    Predicting Risk of Cognitive Impairment With Alzheimer Disease Blood Biomarkers.
    Suzanne E Schindler, David A Wolk.
      
    DOI:  https://doi.org/10.1001/jama.2026.13322
  21. Nat Commun. 2026 Jul 15.
    Integrated two-photon and photoacoustic microscopy for single-cell neurometabolic imaging.
    Jiaxiao Han, Youngseop Lee, Ziang Feng, Yue Wu, Zhuoying Wang, Allison Martinez Mejia, Adam Bauer, Manu Goyal, Jin-Moo Lee, Peinan Zhao, Hao F Zhang, Cheng Sun, Song Hu.
      Understanding how neuronal activity couples with local energy metabolism is fundamental to brain function. Oxygen exchange between individual neurons and red blood cells (RBCs) is central to this process, yet no existing method can simultaneously capture their dynamics at single-cell resolution in vivo. Here, we introduce integrated two-photon and photoacoustic microscopy (TPM-PAM), which enables real-time imaging of single-neuron calcium activity alongside oxygen release from individual RBCs in awake mice. In TPM-PAM, a transparent micro-ring resonator-based ultrasound sensor breaks the long-standing tradeoff between optical access and acoustic sensitivity, while dual-wavelength kymography simultaneously quantifies single-RBC oxygenation and flow to derive the oxygen release rate. Incorporating nonlinear optical manipulation of the neurovascular unit with cellular precision, TPM-PAM reveals distinct neurometabolic responses to whisker stimulation, single-capillary occlusion, and single-neuron stimulation. This work establishes a powerful platform for dissecting neurometabolic coupling at the cellular scale and understanding oxygen-metabolic regulation in brain health and disease.
    DOI:  https://doi.org/10.1038/s41467-026-75603-7
  22. Nat Metab. 2026 Jul 14.
    Macrophage-derived itaconate is a negative regulator of adipose tissue thermogenesis.
    Jiayin Tang, Gerard Pernes, Brenda Nakagaki, Nhien Tran, Laura Bokor, Fran Prenen, Mingyang Yi, Avery E Robertson, Rachel Cronin, Mohamad Sarmini, Jacob Pierscianowski, Victoria Roberts, Birgitta A Ryback, Carl D Novina, Karine Auclair, Haopeng Xiao, Evanna L Mills.
      Thermogenic brown and beige adipose tissues are important in maintaining metabolic health because of their distinct ability to catabolize stored fat and circulating glucose in futile cycles1,2. Macrophages, present in brown adipose tissue, have been reported to both positively and negatively regulate thermogenic adipocyte function through mechanisms that are incompletely understood3-14. Here we show that the macrophage-derived metabolite, itaconate, acts as a paracrine signal to repress adipose tissue thermogenesis in mice. Mechanistically, itaconate inhibits thermogenesis by antagonizing uptake of the pro-thermogenic metabolite, succinate, into brown adipose tissue. These findings reveal an unexpected mechanism for local control of thermogenesis in vivo that relies on paracrine itaconate signalling and demonstrate that the important signalling roles of itaconate extend beyond immunological processes to the regulation of energy balance.
    DOI:  https://doi.org/10.1038/s42255-026-01572-2
  23. Nature. 2026 Jul 16.
    Will making 'replication studies' easier to find help science self-correct?
    Dalmeet Singh Chawla.
      
    Keywords:  Databases; Peer review; Research data
    DOI:  https://doi.org/10.1038/d41586-026-02175-3
  24. Nat Rev Immunol. 2026 Jul 17.
    Macrophages are constitutive architects of tissue integrity.
    Miriam Merad.
      
    DOI:  https://doi.org/10.1038/s41577-026-01334-x
  25. J Clin Invest. 2026 Jul 15. pii: e206628. [Epub ahead of print]136(14):
    Targeting hepatic cholesterol sensing to tackle metabolic dysfunction-associated steatohepatitis.
    Mengwei Zang, Yu Li.
      Metabolic dysfunction-associated steatohepatitis (MASH) affects 1.5%-6.5% of the global population, yet its mechanisms remain incompletely understood. Cholesterol overload is a key driver of MASH, suggesting that targeting cholesterol sensing may offer therapeutic benefits. In this issue, Deng et al. identified nuclear factor erythroid 2-related factor 1 (NFE2L1) as a critical regulator linking cholesterol sensing to VLDL-mediated lipid export. Mechanistically, NFE2L1 interacts with insulin-induced gene 1 (INSIG1) and promotes its degradation in hepatocytes. This cholesterol-dependent NFE2L1-INSIG1 interaction sustains SREBP activation and VLDL secretion to maintain hepatic and systemic lipid homeostasis. Moreover, the study by Deng et al. indicates that hepatic NFE2L1 overexpression decreases INSIG1 abundance and ameliorates MASH progression, highlighting its therapeutic potential.
    DOI:  https://doi.org/10.1172/JCI206628
  26. Nat Cell Biol. 2026 Jul;28(7): 1346
    Cargo capture during ER-phagy.
    Petra Gross.
      
    DOI:  https://doi.org/10.1038/s41556-026-02026-3
  27. Nat Metab. 2026 Jul 14.
    Itaconate as a paracrine brake on thermogenesis.
    Lei-Lei Chen, Dan Ye.
      
    DOI:  https://doi.org/10.1038/s42255-026-01573-1
  28. Science. 2026 Jul 16. 393(6808): 242-243
    Lymph nodes now optional.
    William K Decker.
      A subset of dendritic cells orchestrates the formation of tertiary lymphoid structures in tumor tissues.
    DOI:  https://doi.org/10.1126/science.aei9741
  29. Nat Rev Endocrinol. 2026 Jul 14.
    Lipid sensing and brain hormone receptors in food intake and glucose regulation.
    Ameth N Garrido, Sulayman Aslan Lyons, Dorsa Moslemian, Jacqueline L Beaudry, Tony K T Lam.
      The body possesses critical nutrient sensors that rapidly coordinate feeding behaviour and systemic metabolism through hormones and neural pathways. In this Review, we highlight the mechanisms by which lipid sensing triggers the release of small intestinal-derived cholecystokinin, peptide YY, glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide, as well as kidney-derived growth differentiation factor 15, to regulate satiety and glucose homeostasis through the brain. We discuss how dysregulation of lipid sensing pathways contributes to obesity and type 2 diabetes mellitus, and how interventions including bariatric surgery, modulation of the gut microbiota and pharmacological agonists restore polyhormonal secretion and action on metabolism. We propose that lipid sensing in the small intestine and the kidney orchestrates an endocrine and neural axis that governs energy balance, providing a lipid-sensing-dependent framework for the development of next-generation therapies in obesity and metabolic disease to remotely and concurrently target multiple brain hormone receptors to lower food intake and body weight.
    DOI:  https://doi.org/10.1038/s41574-026-01278-1
  30. Nat Commun. 2026 Jul 17.
    Internalized components of membrane attack complexes disrupt proteostasis and acquire alarmin-like properties.
    Guiyu Song, Zihan Ma, Matthew Fan, Liying He, Yulong Lan, Weihao Li, Zhengtao Jiang, Quan Jiang, Dylan P Noone, Andrea Nans, Kamal L Nahas, Mahsa Nouri Barkestani, Shaoxun Wang, Qianxun Wang, Pengwei Ren, Jolin Cheng, Yinuo Zang, Haitian Zhou, Justin Johnson, Clancy Mullan, Xiangyu Gong, Doryen Bubeck, Gilbert Moeckel, Michael Mak, George Tellides, Dan Jane-Wit.
      Immune effects of membrane attack complexes (MAC) have been widely attributed to their abilities to cause cell death. Here, we show that the MAC component, C9, forms non-cytolytic aggregates with pro-inflammatory effects. Intracellular aggregates of C9 are detected within inflamed tissues of patients in association with endothelial cell (EC) activation but not increased cell death. We identify NUMBL as a Rab35 effector that directly binds surface-bound C9 to promote C9 internalization and entry into the endolysosomal pathway. Within acidified endolysosomes, C9 forms insoluble aggregates that are targeted for degradative aggrephagy in a process that activates NF-κB. For C9 aggrephagy to occur, ZFYVE21, a Rab5 effector, complexes with RNF34 to bridge C9 aggregates to LC3B+ aggresome membranes. We detect C9 aggregates in vivo, and we show that a ZFYVE21-RNF34 signaling axis is required for C9 aggrephagy and NF-κB -dependent EC activation in three separate mouse models. Mice with conditional loss of ZFYVE21 in ECs show reduced aggregraphy, resulting in attenuated systemic inflammation and reduced tissue injury following skin transplantation. Our data show that the C9 component of MACs forms intracellular aggregates with alarmin-like properties.
    DOI:  https://doi.org/10.1038/s41467-026-75696-0
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