bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2026–04–19
25 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. PANoptosis fuels the fire of arthritis.
  2. The dual role of TOX in regulating TH1 and CD8+ T cell fate.
  3. A picture of health: gene-expression maps of the human liver from living donors.
  4. Astrocyte-based CAR immunotherapy against Alzheimer's disease.
  5. mRNA vaccines engage unconventional pathways in CD8+ T cell priming.
  6. Exoproteome of calorie-restricted humans identifies complement deactivation as an immunometabolic checkpoint reducing inflammaging.
  7. Therapeutic mitochondria transplants made more efficient with targeting tool.
  8. Diet-induced metabolic memory shapes CD8+ T cell ferroptosis susceptibility.
  9. Huge analysis of 320,000 careers suggests that productive researchers stay that way.
  10. Oxytocin signaling in adipocytes is required for normal milk fat production.
  11. A fast way to lose antibodies.
  12. The autoantigen TRIM21 assembles proinflammatory immune complexes after lytic cell death.
  13. The weight-loss-independent hepatoprotective benefits of semaglutide are orchestrated by intrahepatic sinusoidal endothelial GLP-1 receptors.
  14. The genetic basis for DNA methylation variation across tissues and development.
  15. Runx writes the RORγt code for immune tolerance.
  16. Deep single-cell decoding of human pancreatic islets reveals T2D β-cell gene expression defects.
  17. p21+TREM2+ senescent macrophages fuel inflammaging and metabolic dysfunction-associated steatotic liver disease.
  18. Mitochondrial translation elongation controls OXPHOS biogenesis by coordinating synthesis and folding of mitochondrially encoded proteins.
  19. Cell-type-targeted mitochondrial transplantation rescues cell degeneration.
  20. Training, memory, and tissue adaptation of NK cells and innate lymphoid cells.
  21. Hepatic glutathione depletion ameliorates MASLD through selective protein oxidation and inhibition of lipogenesis.
  22. Purine salvage pathway protects CD8+ T cells from metabolic stress.
  23. Metabolically Healthy Obesity in Children Still Raises Cardiometabolic Risk.
  24. Lipid-trap mass spectrometry identifies lipid-protein interactions in cells.
  25. Longitudinal multimorbidity trajectories shape personalized glycaemic patterns.
  1. Immunity. 2026 Apr 14. pii: S1074-7613(26)00128-7. [Epub ahead of print]59(4): 931-933
    PANoptosis fuels the fire of arthritis.
    Nagakannan Pandian, Thirumala-Devi Kanneganti.
      Innate immune cell death is critical for host defense but drives inflammatory disease when dysregulated. In this issue of Immunity, Huang et al. report that the complement protein C1q activates macrophage mitochondrial SARM1 to deplete NAD+ and produce cADPR, triggering NLRC5/NLRP12-PANoptosome formation, PANoptosis, and synovial inflammation in rheumatoid arthritis; targeting this pathway reduces inflammation.
    DOI:  https://doi.org/10.1016/j.immuni.2026.03.017
  2. Nat Immunol. 2026 Apr 13.
    The dual role of TOX in regulating TH1 and CD8+ T cell fate.
    Yoon-Chul Kye, Vijay K Kuchroo.
      
    DOI:  https://doi.org/10.1038/s41590-026-02494-7
  3. Nature. 2026 Apr 15.
    A picture of health: gene-expression maps of the human liver from living donors.
      
    Keywords:  Diseases; Physiology; Transcriptomics
    DOI:  https://doi.org/10.1038/d41586-026-01187-3
  4. Nat Aging. 2026 Apr 14.
    Astrocyte-based CAR immunotherapy against Alzheimer's disease.
    Maria Papatriantafyllou.
      
    DOI:  https://doi.org/10.1038/s43587-026-01115-0
  5. Nature. 2026 Apr 15.
    mRNA vaccines engage unconventional pathways in CD8+ T cell priming.
    Suin Jo, Lijin Li, Chandrani Thakur, Kevin A Telfer, Hussein Sultan, Ray A Ohara, Michelle He, Giri Nam, Jing Chen, Feiya Ou, Monia Draghi, Nicholas M Valiante, Robert D Schreiber, Gwendalyn J Randolph, Naresha Saligrama, Theresa L Murphy, William E Gillanders, Kenneth M Murphy.
      Vaccines composed of mRNA and lipid nanoparticles (LNPs) activate B cells and T cells by inducing in vivo production of specific protein antigens. While B cells can be activated directly by antigens, T cell activation requires antigen processing and presentation by MHC molecules on specialized antigen-presenting cells (APCs). In response to viral infections, tumours, and protein- and cDNA-based vaccines, antigen presentation to CD8+ T cells is particularly dependent on type 1 conventional dendritic (cDC1) cells, which are specialized for efficient cross-presentation of exogenous antigens1-4. However, whether similar mechanisms have a role in mRNA-LNP vaccination is unclear. Here we report that mRNA-LNP vaccines do not require cDC1 cells or the WDFY4-dependent cross-presentation pathway for CD8+ T cell priming but instead engage both cDC1 and cDC2 cells redundantly. While CD8+ T cells primed exclusively by either cDC1 or cDC2 cells showed phenotypic differences, both could mediate anti-tumour responses and memory formation. Importantly, acquisition by cDCs of peptide-MHC-I complexes from non-haematopoietic cells, called cross-dressing, provides a substantial component of CD8+ T cell priming, in a manner dependent on type I interferon. mRNA-LNP induction of cross-dressing might explain their ability to activate CD8+ T cells against antigens not encoded by the vaccine.
    DOI:  https://doi.org/10.1038/s41586-026-10353-6
  6. Nat Aging. 2026 Apr 13.
    Exoproteome of calorie-restricted humans identifies complement deactivation as an immunometabolic checkpoint reducing inflammaging.
    Manish Mishra, Hee-Hoon Kim, Yun-Hee Youm, Elsie Gonzalez-Hurtado, Konstantin Zaitsev, Tamara Dlugos, Irina Shchukina, Christy Gliniak, Eric Ravussin, Subhasis Mohanty, Albert C Shaw, Philipp E Scherer, Maxim N Artyomov, Vishwa Deep Dixit.
      Caloric restriction (CR) extends lifespan across diverse organisms, but the effects of CR on human aging and on healthspan are only beginning to be uncovered. In this study, we applied proteomics to plasma samples collected longitudinally from participants achieving, on average, 14% CR over 2 years as part of the CALERIE trial. We identified that inhibition of the complement pathway is linked to lower inflammaging. In humans, the C3a/C3 ratio was significantly lowered by CR, thus reducing inflammation emanating from three canonical complement pathways. Furthermore, circulating C3a is elevated during aging in humans and in mice; we identified a non-senescent age-associated macrophage subset that expands in visceral fat as the predominant source. In macrophages, C3a-C3AR1 autocrine signaling via extracellular signal-regulated kinase (ERK) regulates age-related inflammation. Intra-adipose administration of a C3a-specific neutralizing antibody reduced inflammaging in mice. In addition, fibroblast growth factor 21 (FGF21) overexpression and deficiency of phospholipase A2 group VII (PLA2G7/lp-PLA2), which enhance lifespan and healthspan in mice, lowered C3a in aging. Thus, complement C3a reduction is a metabolically regulated inflammatory checkpoint that can be harnessed to attenuate inflammaging.
    DOI:  https://doi.org/10.1038/s43587-026-01107-0
  7. Nature. 2026 Apr 15.
    Therapeutic mitochondria transplants made more efficient with targeting tool.
    Samantha J Krysa, Jonathan R Brestoff.
      
    Keywords:  Biotechnology; Cell biology; Diseases
    DOI:  https://doi.org/10.1038/d41586-026-00910-4
  8. Nat Immunol. 2026 Apr 13.
    Diet-induced metabolic memory shapes CD8+ T cell ferroptosis susceptibility.
    Ryan P Mansell, Whitney S Henry.
      
    DOI:  https://doi.org/10.1038/s41590-026-02493-8
  9. Nature. 2026 Apr 13.
    Huge analysis of 320,000 careers suggests that productive researchers stay that way.
    Andy Tay.
      
    Keywords:  Careers; Funding; Lab life
    DOI:  https://doi.org/10.1038/d41586-026-00744-0
  10. Cell Metab. 2026 Apr 16. pii: S1550-4131(26)00107-5. [Epub ahead of print]
    Oxytocin signaling in adipocytes is required for normal milk fat production.
    Erwei Li, Yangmian Yuan, Haijing Sun, Khushi Patel, Nan Zhang, Soumya Nagesh, Juan J Aristizabal-Henao, Michael Kiebish, Christopher Jacobs, Dave Bridges, Brigid Gregg, Evan D Rosen.
      Milk triglycerides, a crucial nutrient source for newborn mammals, can be derived from adipose lipolysis, dietary sources, or de novo synthesis in mammary epithelial cells (MECs). Here, we identify a critical role for the neuropeptide oxytocin (OXT) in providing milk triglyceride needed to sustain neonatal growth, mediated by its actions on adipose lipolysis. Dams lacking OXT receptors (OXTRs) specifically in adipocytes (OxtrΔAd) give birth to pups with reduced weight gain. Oxytocinergic sympathetic neurons are the relevant source of OXT mediating this effect. Milk from OxtrΔAd dams was deficient in triglycerides, which could be rescued by liberalizing dietary fat intake. Finally, single-cell analysis of lactating mammary glands from OxtrΔAd dams revealed a profound shift in the metabolic programming of MECs, indicative of reduced mTOR signaling, increased autophagy, and reduced lipid synthesis. These findings highlight the critical role of OXT-mediated adipose lipolysis in mammalian lactation, demonstrating that lipolysis-derived free fatty acids (FFAs) are essential for normal milk fat and neonatal health.
    Keywords:  growth restriction; lactation; lipolysis; mammary gland; milk lipid; oxytocin
    DOI:  https://doi.org/10.1016/j.cmet.2026.03.013
  11. Immunity. 2026 Apr 14. pii: S1074-7613(26)00129-9. [Epub ahead of print]59(4): 934-936
    A fast way to lose antibodies.
    Sheenam Verma, Oliver J Harrison.
      Long-lived plasma cells maintain antibody titers that sustain humoral immunity, yet the physiological cues regulating their persistence remain incompletely understood. In this issue of Immunity, Zhu et al. reveal that fasting-induced β-hydroxybutyrate destabilizes bone marrow plasma cell niches through HCAR2 signaling, accelerating the loss of long-lived plasma cells and humoral immunity.
    DOI:  https://doi.org/10.1016/j.immuni.2026.03.018
  12. Sci Immunol. 2026 Apr 17. 11(118): eads9680
    The autoantigen TRIM21 assembles proinflammatory immune complexes after lytic cell death.
    Esther L Jones Evans, Benjamin Demarco, Han Cai, Madelon M E de Jong, Sarah Hill, Marcus A Widdess, Joannah R Fergusson, Ryan E Glass, Gemma Harris, Gracie J Mead, Yavuz F Yazicioglu, Saba Nayar, Benjamin A Fisher, Mark S Cragg, Alexander J Clarke, Audrey Gérard, Jelena S Bezbradica, Lynn B Dustin.
      Sjögren's disease (SjD) causes localized and systemic inflammation and autoantibody production against intracellular proteins such as TRIM21/Ro52 (tripartite motif-containing protein 21). TRIM21, an E3 ubiquitin ligase, binds antibody Fc domains on opsonized pathogens that have escaped extracellular immunity and entered the cytosol. TRIM21 then ubiquitinates these pathogens, driving their proteasomal degradation. How TRIM21 becomes an autoantigen remains unclear. We show that TRIM21 is released upon lytic cell death (pyroptosis or necroptosis) but not apoptosis. Although many cytosolic proteins are released by dead cells, liberated TRIM21 is distinct: Its high antibody affinity enables binding to Fc domains of circulating immunoglobulins, forming large immune complexes (ICs). These ICs increase in SjD, where anti-TRIM21 autoantibodies interact with released TRIM21 via Fc and F(ab')2. TRIM21 ICs are taken up by macrophages, which drive proinflammatory responses, antigen presentation, and metabolic changes in high interferon environments. Thus, TRIM21 may perpetuate inflammation and autoantigen presentation, resulting in high immunogenicity.
    DOI:  https://doi.org/10.1126/sciimmunol.ads9680
  13. Cell Metab. 2026 Apr 14. pii: S1550-4131(26)00105-1. [Epub ahead of print]
    The weight-loss-independent hepatoprotective benefits of semaglutide are orchestrated by intrahepatic sinusoidal endothelial GLP-1 receptors.
    Maria J Gonzalez-Rellan, Cristina Riobello, Susanna Fang, Eloisa Martins da Silva, Jacqueline A Koehler, Rui Shang, Rola Hammoud, Xiemin Cao, Marta Varela-Rey, Daniel J Drucker.
      Glucagon-like peptide-1 (GLP-1) medicines improve metabolic liver disease through weight-loss-dependent and -independent actions. Here, we interrogated semaglutide's action in mice with metabolic dysfunction-associated steatohepatitis (MASH). In Glp1rWnt1-/- mice resistant to GLP-1RA-induced weight loss, semaglutide improved steatosis, fibrosis, and immune remodeling. GEM-X Flex-seq localized Glp1r expression to pericentral liver sinusoidal endothelial cells (ECs) (LSECs) and CD8+ T cells. EC Glp1r deletion in Glp1rTie2-/- mice or AAV8-Cre-mediated hepatic EC Glp1r knockdown substantially abrogated semaglutide's hepatic benefits despite preserved weight loss. Transcriptomic profiling revealed that Glp1r+ LSECs adopt a stress-responsive phenotype in MASH that is reversed by semaglutide. Glp1r+ LSECs function as dominant contributors to semaglutide-regulated circuits linked to injury and repair involving VWF, SELE, CEACAM, and BMP. Molecular profiling revealed semaglutide-coordinated transcriptional and protein-level reversal of disease signatures. Together, the data using mouse models of MASH reveal an EC-specific, weight-loss-independent, semaglutide-regulated, GLP-1R-dependent intrahepatic network for improving liver health.
    Keywords:  GLP-1; LSEC; MASH; diabetes; inflammation; liver; obesity; semaglutide
    DOI:  https://doi.org/10.1016/j.cmet.2026.03.011
  14. Nat Commun. 2026 Apr 15.
    The genetic basis for DNA methylation variation across tissues and development.
    Jonathan Rosenski, Ofra Sabag, Eitan Marcus, Netanel Loyfer, Yuval Dor, Howard Cedar, Tommy Kaplan.
      The mechanisms by which genetic variation shapes the epigenome across cell types and developmental stages have remained elusive. Here, we define a unifying developmental framework for DNA methylation programming, grounded in genome-wide methylation and genetic variation data from both mouse and human. In mice, we identify thousands of differentially methylated regions (DMRs) linked to sequence polymorphisms that disrupt transcription factor binding. These DMRs are programmed either during implantation or later in organogenesis, revealing two distinct periods of epigenetic regulation. Extending this logic to humans, we analyze our atlas of over 200 WGBS samples from 39 purified cell types and map 33,574 regions where common SNPs control allele-specific methylation. These include both early-established and cell-type-specific loci, many of which colocalize with eQTLs, enhancers, silencers, and disease-associated variants. Our results uncover a widespread mechanism by which genetic variation influences the regulatory landscape, linking sequence, methylation, and transcription across tissues. This cross-species atlas of sequence-dependent methylation not only clarifies the logic and timing of epigenetic programming, but also provides a foundational resource for deciphering non-coding variants in development, complex disease, and regenerative medicine.
    DOI:  https://doi.org/10.1038/s41467-026-71693-5
  15. Immunity. 2026 Apr 14. pii: S1074-7613(26)00132-9. [Epub ahead of print]59(4): 928-930
    Runx writes the RORγt code for immune tolerance.
    Chrysothemis C Brown.
      RORγt is a key transcriptional regulator across diverse immune subsets. In this issue of Immunity, Fukui et al. show how Runx controls RORγt expression during early development and link progenitor specification to the diversification of RORγt+ innate immune lineages.
    DOI:  https://doi.org/10.1016/j.immuni.2026.03.021
  16. EMBO J. 2026 Apr 15.
    Deep single-cell decoding of human pancreatic islets reveals T2D β-cell gene expression defects.
    Khushdeep Bandesh, Efthymios Motakis, Siddhi Nargund, Romy Kursawe, Vijay Selvam, Ansarullah, Redwan M Bhuiyan, Giray Naim Eryilmaz, Amelia M Willett, Jacqueline K White, Sai Nivedita Krishnan, Cassandra N Spracklen, Duygu Ucar, Michael L Stitzel.
      Pancreatic islets maintain glucose homeostasis through coordinated action of endocrine and affiliate cell types and are central to type 2 diabetes (T2D) genetics and pathophysiology. Our understanding of robust human islet cell type-specific alterations in T2D remains limited. Here, we report comprehensive single-cell transcriptome profiling of 245,878 human islet cells from 48 donors spanning non-diabetic, pre-diabetic, and T2D states, and we identify 14 distinct cell types detected in every donor. Cell-cluster analysis reveals ~25-30% β-cell reductions consisting of β-cell loss and proportional increases in a senescent β-cell subpopulation in T2D donors, consistent with previous reports. Further, comparative data integration identifies 511 differentially expressed genes (DEGs) in T2D β-cells, including T2D-associated vitamin A metabolism genes, which are linked to impaired β-cell viability by multimodal functional validation. Integration with T2D genetic, proteomic, and mouse model metabolic phenotypes nominates 58 candidate causal T2D genes, including PDZK1 and GRAMD2B, which preserve β-cell mass. Together, this genomic resource provides an enhanced type 2 diabetes expression-atlas for data exploration, analysis, and hypothesis testing, as well as a novel genomic resource for insights into T2D pathophysiology and human islet dysfunction.
    Keywords:   GRAMD2B ; Beta-cell Death; Human Islet scRNA-seq; Type 2 Diabetes (T2D); Vitamin A Metabolism
    DOI:  https://doi.org/10.1038/s44318-026-00744-w
  17. Nat Aging. 2026 Apr 16.
    p21+TREM2+ senescent macrophages fuel inflammaging and metabolic dysfunction-associated steatotic liver disease.
    Ivan A Salladay-Perez, Itzetl Avila, Lizeth Estrada, Andreea C Alexandru, Cristian Ponce, Anika Dhingra, Grasiela Torres, Christina Y Deng, Ronak Hegde, Julia Gensheimer, Abhijit Kale, Indra Heckenbach, Simon Hui, Chantle Edillor, Jose A Soto, Alexander J Napior, Isaiah Little, Mark Larsen, Jacob Rose, Lia Farahi, Edwin D J Lopez Gonzalez, Matthew R Krieger, Kushan Chowdhury, Mridul Sharma, Yuming Jiang, Kevin Williams, Morten Scheibye-Knudsen, Carla M Koehler, Jesse G Meyer, Julia J Mack, Charles Brenner, Steven J Bensinger, Cyril Lagger, João Pedro de Magalhães, Birgit Schilling, Rajat Singh, Eric Verdin, Aldons J Lusis, Anthony J Covarrubias.
      Cellular senescence drives chronic sterile inflammation during aging via the senescence-associated secretory phenotype, yet the senescent cell types responsible are poorly defined. Macrophages share multiple features of senescence, including inflammatory secretion, yet whether macrophages can adopt a senescent state remains unclear. Here we identify p21⁺Trem2⁺ senescent macrophages as a major source of inflammaging, using primary mouse and human macrophage models of DNA damage and cholesterol-induced senescence characterized by multi-omic profiling. We found that senescent macrophages exhibit a distinctive p21-TREM2 expression profile and senescence-associated secretory phenotype, driven in part by type I interferon signaling via cytosolic mitochondrial DNA. We also found that senescent macrophage accumulation occurs in aging, metabolic dysfunction-associated steatotic liver disease mouse livers, and is enriched in human cirrhotic liver tissue. Finally, senolytic treatment targeting senescent macrophages reduced liver inflammation and steatosis in both aged mice and mice with metabolic dysfunction-associated steatotic liver disease. These findings establish macrophage senescence as a central driver of chronic inflammation in aging and metabolic liver disease, and a tractable therapeutic target.
    DOI:  https://doi.org/10.1038/s43587-026-01101-6
  18. Mol Cell. 2026 Apr 16. pii: S1097-2765(26)00193-0. [Epub ahead of print]86(8): 1511-1528.e12
    Mitochondrial translation elongation controls OXPHOS biogenesis by coordinating synthesis and folding of mitochondrially encoded proteins.
    Lvxin Xie, Shuchao Ren, Li Zhang, Ziqing Wang, Tong Wu, Qing Dai, Shikun Xiang, Zhihua Qian, Yufan Xian, Shutong Xu, Xiao-Lin Chen, Chuan He, Yi Liu, Zhipeng Zhou.
      Mitochondria generate ATP through oxidative phosphorylation (OXPHOS), with core structural subunits encoded by mitochondrial DNA (mtDNA) and translated by mitochondrial ribosomes. However, how mitochondrial translation elongation influences OXPHOS biogenesis remains unclear. Here, we show that in Neurospora crassa, the mitochondrial ribosomal RNA (rRNA) methyltransferase 1 (MRM1) promotes OXPHOS biogenesis by repressing translation elongation independently of its catalytic activity. The N-terminal intrinsically disordered region (IDR) of MRM1 binds simultaneously to mitochondrial ribosomes and mRNAs. Disrupting either interaction accelerates elongation and enhances synthesis of mtDNA-encoded OXPHOS subunits but impairs their co-translational folding and membrane insertion. Pharmacological slowing of mitochondrial translation partially alleviates these defects. The MRM1 IDR is conserved in Ascomycete fungi and is essential for plant infection by Magnaporthe oryzae. Together, our findings identify translation elongation control as a mechanism coordinating mitochondrial protein synthesis and folding during OXPHOS biogenesis and MRM1 as a potential target for broad-spectrum antifungal strategies.
    Keywords:  Magnaporthe oryzae; Neurospora crassa; mitochondrial rRNA methyltransferase; mitochondrial translation; oxidative phosphorylation; protein folding; translation elongation
    DOI:  https://doi.org/10.1016/j.molcel.2026.03.017
  19. Nature. 2026 Apr 15.
    Cell-type-targeted mitochondrial transplantation rescues cell degeneration.
    Temurkhan Ayupov, Verónica Moreno-Juan, Serena Curtoni, Alex Fratzl, Upnishad Sharma, Susana Posada-Céspedes, Ramona Ratiu, Rei Morikawa, Alexandra Graff Meyer, Margherita Pezzoli, Glenn Bantug, Morgan Chevalier, Yanyan Hou, Sarah A Nadeau, Álvaro Herrero-Navarro, Vikram Ayinampudi, Elizabeth Kastanaki, Natasha Whitehead, Rebecca A Siwicki, Mariana M Ribeiro, Ji Hoon Han, Annalisa Bucci, Christoph Hess, Simone Picelli, Magdalena Renner, Daniel J Müller, Cameron S Cowan, Simon Hansen, Botond Roska.
      A number of currently untreatable diseases, including neurodegenerative disorders, optic nerve atrophy and heart failure, are associated with mitochondrial dysfunction. Transplantation of healthy mitochondria has been proposed as a potential therapeutic strategy1-3. However, the lack of methods to target donor mitochondria to disease-affected cell types limits treatment specificity and efficacy. Here we developed MitoCatch as a system to deliver mitochondria to specific cell types using different types of protein binders. Donor mitochondria are captured by target cells by cell-surface-displayed monospecific binders, mitochondrion-displayed monospecific binders or bispecific binders linking mitochondria to target cells. Using MitoCatch, we show that donor mitochondria are efficiently internalized, exposed to the cytosol, move, and undergo fusion and fission inside target cells. By engineering binders with different affinities, we tune the efficiency of mitochondrial delivery. We demonstrate targeted mitochondrial transplantation to retinal cell types, neurons and cardiac, endothelial and immune cells in humans and mice. Transplanted mitochondria promoted the survival of damaged neurons from an individual with optic nerve atrophy in vitro and after neuronal injury in mice in vivo. MitoCatch is a potential strategy to target disease-affected cell types with mitochondria in organs affected by diseases associated with mitochondrial dysfunction.
    DOI:  https://doi.org/10.1038/s41586-026-10391-0
  20. Immunity. 2026 Apr 14. pii: S1074-7613(26)00124-X. [Epub ahead of print]59(4): 911-927
    Training, memory, and tissue adaptation of NK cells and innate lymphoid cells.
    Georg Gasteiger, Thomas Ossner, Christin Friedrich.
      Innate lymphoid cells (ILCs) and natural killer (NK) cells can acquire durable functional changes following activation. These include features of trained immunity, such as epigenetic reprogramming and poised effector states, and of adaptive immune memory, including clonal-like expansion and acquired tissue residency. Together, these features enable adaptation of NK/ILC populations and their contributions to tissue homeostasis, immune surveillance, and secondary responses. Reciprocally, local niches are reshaped by inflammatory episodes, influencing immune cell behavior beyond resolution. Here, we discuss the layers of memory-like features in innate lymphocytes, highlighting emerging questions of NK/ILC differentiation and reprogramming, as well as their residency, interactions, and functions in tissues. We explore how immune experience modulates these processes, with implications for inflammatory diseases, vaccination, and immunotherapy.
    Keywords:  NK cells; innate lymphoid cells; innate memory; tissue-circuits
    DOI:  https://doi.org/10.1016/j.immuni.2026.03.013
  21. J Clin Invest. 2026 Apr 15. pii: e197556. [Epub ahead of print]136(8):
    Hepatic glutathione depletion ameliorates MASLD through selective protein oxidation and inhibition of lipogenesis.
    Xiang-Yu Liu, Guoxiao Wang, Yingying Yu, Haopeng Xiao, Kentaro Oh-Hashi, Xu Shi, Shuning Zheng, Robert Gerszten, C Ronald Kahn.
      Glutathione (GSH) maintains a reduced cellular environment and is widely believed to mitigate disease-associated oxidative damage to proteins, thereby protecting against metabolic dysfunction-associated steatotic liver disease (MASLD). However, this widely accepted assumption remains largely untested because of challenges in physiologically manipulating hepatic GSH levels during disease development. Here, we have utilized liver-specific overexpression of cation transport regulator homolog 1 (Chac1), a recently identified intracellular GSH-degrading enzyme, to induce hepatic GSH depletion during MASLD progression. Contrary to canonical doctrine, GSH depletion unexpectedly protects against MASLD by substantially decreasing hepatic lipogenesis and fibrosis without triggering an oxidative stress response. Mechanistically, GSH depletion does not cause global protein oxidation but instead selectively oxidizes and destabilizes fatty acid synthase while decreasing lipogenic gene expression at the transcriptional level, collectively suppressing lipogenesis. Interestingly, Chac1 expression is decreased in livers of patients with MASLD, highlighting its potential therapeutic relevance. These findings revise the conventional view of GSH in protein redox and demonstrate that targeted redox manipulation through GSH depletion protects against MASLD.
    Keywords:  Cell biology; Hepatology; Metabolism; Metabolomics
    DOI:  https://doi.org/10.1172/JCI197556
  22. Nat Immunol. 2026 Apr 13.
    Purine salvage pathway protects CD8+ T cells from metabolic stress.
    Masaki Tajima, He Hao, Baihao Zhang, Yuta Matsuoka, Kazuhiro Sonomura, Koshi Imami, Yosuke Isobe, Rae Maeda, Yu-Hsien Lin, Akihiro Shimba, Ryoma Kato, Pedro Henrique Costa Cruz, Sayaka Washizu, Yosuke Ikejiri, Akiyo Morinibu, Clive Steven Barker, Jun Seita, Yibo Wu, Satomi Ito, Seiko Narushima, Rei Nakano, Mikako Maruya, Wakana Kobayashi, Sai Shanmukha Priya Narayanan, Jumana Shaheen, Hiroyuki Neyama, Ken-Ichi Yamada, Makoto Arita, Yuki Sugiura, Sidonia Fagarasan.
      Metabolic stress from a high-fat diet (HFD) impairs antitumor immunity through persistent metabolic rewiring, but its effects and long-term impact on CD8+ T cell metabolism remain unknown. Here, we found that even temporary exposure to a HFD impaired antitumor immunity 10 weeks after reversion to a normal diet. This was due to lasting metabolome changes that included enrichment in phospholipids sensitive to peroxidation and depletion of antioxidants, affecting the survival and function of CD8+ T cells. Under oxidative stress, CD8+ T cells utilized the xanthine salvage pathway to produce guanosine triphosphate, enhancing the amount of tetrahydrobiopterin. Xanthine supplementation reduced lipid peroxidation in tumor-draining lymph nodes and improved antitumor immunity in mice previously on a HFD. Our data indicate that metabolic stress in CD8+ T cells persists long after restoration of a balanced diet, and manifests as vulnerability to ferroptosis, which could be mitigated by replenishing biopterins through the xanthine salvage pathway.
    DOI:  https://doi.org/10.1038/s41590-026-02491-w
  23. JAMA. 2026 Apr 17.
    Metabolically Healthy Obesity in Children Still Raises Cardiometabolic Risk.
    Samantha Anderer.
      
    DOI:  https://doi.org/10.1001/jama.2026.2112
  24. Nat Cell Biol. 2026 Apr 13.
    Lipid-trap mass spectrometry identifies lipid-protein interactions in cells.
    Andrea Paquola, Clare E Benson, Smita Eknath Desale, Cagakan Ozbalci, Elisabeth M Storck, Stephen J Terry, Bhagyashree Dasari Rao, Kelechi N Nwite, Federica Ferrentino, Ulrike S Eggert.
      Cells actively maintain complex lipidomes that encompass thousands of lipids; however, many of the roles of these lipids remain unexplored. Specific interactions between lipids and membrane proteins are a likely reason for lipidome complexity. Here we report the development of a technique, named lipid-trap mass spectrometry (LTMS), to systematically study lipid-protein interactions directly captured from mammalian cells. LTMS uses immunoprecipitation of GFP-tagged proteins expressed in HeLa cells, followed by lipidomic analysis of lipids bound to the GFP-tagged protein. We applied LTMS to cell division to illustrate the technique. We chose this process because membranes regulate their lipid composition as they undergo major changes during cytokinesis, and many cytokinetic proteins, including RACGAP1 and ESCRT-III components CHMP4B and CHMP2A, are membrane-associated. Using LTMS, we found that RACGAP1 and CHMP4B associate with specific lipid species in dividing compared with non-dividing cells. We expand our understanding of lipid diversity during cell division and present a general approach to explore lipid-protein interactions to further our knowledge of the roles of lipids in mammalian cells.
    DOI:  https://doi.org/10.1038/s41556-026-01928-6
  25. Nat Metab. 2026 Apr 16.
    Longitudinal multimorbidity trajectories shape personalized glycaemic patterns.
    Ke Zhang, Jieteng Chen, Yan Yan, Huijun Wang, Zelei Miao, Wanglong Gou, Congmei Xiao, Ruiqi Shi, Xiaofang Jia, Wenwen Du, Yujing Huang, Tiannan Guo, Chang Su, Yuanqing Fu, Yu-Ming Chen, Ju-Sheng Zheng.
      Older individuals often live with diverse combinations of chronic diseases. However, whether multimorbidity contributes to glycaemic dysregulation remains unclear. Here we show that cumulative disease trajectories shape interindividual glycaemic variability throughout the ageing process. Tracking 1,398 participants in the Guangzhou Nutrition and Health Study cohort over 12 years, we develop a systemic multimorbidity index (MMI-system) that reflects the cumulative burden of chronic disorders. We also measure individual glycaemic dynamics and responses to dietary challenges using continuous glucose monitoring at the latest follow-up visit (mean age, 69.2 years). MMI-system exhibits dose-dependent associations with glycaemic variability and sensitivity to dietary challenges, independent of diabetes status. Longitudinal proteome mapping reveals that lipid homeostasis proteins explain 12.9% of the association between MMI-system and personalized dietary responses. These findings are independently validated in the China Health and Nutrition Survey cohort. Overall, our study suggests that integrating longitudinal multimorbidity profiling with circulating proteomics may enhance precision glycaemic management, offering actionable insights for dietary interventions in the older population.
    DOI:  https://doi.org/10.1038/s42255-026-01512-0
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