bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2025–06–08
27 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Male mice can grow ovaries if their pregnant mums are iron deficient.
  2. Immuno-amnesia: Without B cells, T cells cannot remember.
  3. CAR T cells affect cognition.
  4. Succinate undermines FOXP3 stability and disrupts Treg cell function.
  5. The microRNA miR-30a blocks adipose tissue fibrosis accumulation in obesity.
  6. Secretion of nuclear DNA regulates leukotriene B4 levels to resolve inflammation.
  7. Tumor lipids suppress NK cells.
  8. Fetal Treg cell reprogramming links maternal immunity to neurodevelopment.
  9. ROMO1 overexpression protects the mitochondrial cysteinome from oxidations in aging.
  10. Lactate dehydrogenase B facilitates disulfidptosis and exhaustion of tumour-infiltrating CD8+ T cells.
  11. The complex role of brain cilia in feeding control.
  12. Iron deficiency in pregnant mice causes XY embryos to develop with female characteristics.
  13. Inhibition of Cholesterol Synthesis in T Cells Protects the Liver Against Steatosis, Inflammation, and Oxidative Stress in Metabolic Dysfunction-Associated Steatohepatitis.
  14. Structural insights into human Pol III transcription initiation in action.
  15. Base editors model mitochondrial disease.
  16. Cysteine depletion triggers adipose tissue thermogenesis and weight loss.
  17. Serotonergic neurons regulate the Drosophila vascular niche to control immune stress hematopoiesis.
  18. Male mice can grow female organs - if their mothers lack iron.
  19. Is taurine an aging biomarker?
  20. The People-First Liver Charter.
  21. Neuronal aging causes mislocalization of splicing proteins and unchecked cellular stress.
  22. Individual variations in glycemic responses to carbohydrates and underlying metabolic physiology.
  23. Increased inflammation as well as decreased endoplasmic reticulum stress and translation differentiate pancreatic islets from donors with pre-symptomatic stage 1 type 1 diabetes and non-diabetic donors.
  24. Panose prevents acute-on-chronic liver failure by reducing bacterial infection in mice.
  25. Assessing the health of the gut microbial organ: why and how?
  26. Metabolic switches in cell death regulation.
  27. Brown adipose tissue secretes OLFM4 to coordinate sensory and sympathetic innervation via Schwann cells.
  1. Nature. 2025 Jun 04.
    Male mice can grow ovaries if their pregnant mums are iron deficient.
    Rachel Fieldhouse.
      
    Keywords:  Genetics; Medical research
    DOI:  https://doi.org/10.1038/d41586-025-01740-6
  2. Sci Immunol. 2025 Jun 06. 10(108): eadz3620
    Immuno-amnesia: Without B cells, T cells cannot remember.
    Jonathan S Maltzman.
      Why B cells are needed for optimal CD8 T cell memory.
    DOI:  https://doi.org/10.1126/sciimmunol.adz3620
  3. Nat Immunol. 2025 Jun;26(6): 807
    CAR T cells affect cognition.
    Paula Jauregui.
      
    DOI:  https://doi.org/10.1038/s41590-025-02188-6
  4. Nat Immunol. 2025 Jun;26(6): 817-818
    Succinate undermines FOXP3 stability and disrupts Treg cell function.
    Ye Zheng.
      
    DOI:  https://doi.org/10.1038/s41590-025-02167-x
  5. J Clin Invest. 2025 Jun 05. pii: e175566. [Epub ahead of print]
    The microRNA miR-30a blocks adipose tissue fibrosis accumulation in obesity.
    Pradip K Saha, Robert Sharp, Aaron R Cox, Rabie Habib, Michael J Bolt, Jessica B Felix, Claudia E Ramirez Bustamante, Xin Li, Sung Yun Jung, Kang Ho Kim, Kai Sun, Huaizhu Wu, Samuel Klein, Sean M Hartig.
      White adipose tissue (WAT) fibrosis occurring in obesity contributes to the inflammatory and metabolic co-morbidities of insulin resistance and type 2 diabetes, yet the mechanisms involved remain poorly understood. Here, we report a role for the broadly conserved microRNA miR-30a as a regulator of WAT fibrosis and systemic glucose metabolism. Mice modified to express miR-30a at elevated levels in adipose tissues maintain insulin sensitivity coupled with reduced fatty liver disease when fed high fat diet. These effects were attributable to cell-autonomous functions of miR-30a that potently increase expression of adipocyte-specific genes. Proteomic screening revealed miR-30a limits pro-fibrotic programs in subcutaneous WAT, at least in part, by repressing PAI-1, a dominant regulator of fibrinolysis and biomarker of insulin resistance. Conversely, mouse adipocytes lacking miR-30a exhibited greater expression of fibrosis markers with disrupted cellular metabolism. Lastly, miR-30a expression negatively correlates with PAI-1 levels in subcutaneous WAT from people with obesity, further supporting an anti-fibrotic role for miR-30a. Together, these findings uncover miR-30a as a critical regulator of adipose tissue fibrosis that predicts metabolically healthy obesity in people and mice.
    Keywords:  Adipose tissue; Cell biology; Fibrosis; Metabolism; Noncoding RNAs
    DOI:  https://doi.org/10.1172/JCI175566
  6. Nat Cell Biol. 2025 Jun 02.
    Secretion of nuclear DNA regulates leukotriene B4 levels to resolve inflammation.
      
    DOI:  https://doi.org/10.1038/s41556-025-01681-2
  7. Nat Immunol. 2025 Jun;26(6): 807
    Tumor lipids suppress NK cells.
    Stephanie Houston.
      
    DOI:  https://doi.org/10.1038/s41590-025-02186-8
  8. Nat Rev Immunol. 2025 Jun 02.
    Fetal Treg cell reprogramming links maternal immunity to neurodevelopment.
    Mahdieh Golzari-Sorkheh, Juan Carlos Zúñiga-Pflücker.
      
    DOI:  https://doi.org/10.1038/s41577-025-01194-x
  9. Nat Commun. 2025 Jun 03. 16(1): 5133
    ROMO1 overexpression protects the mitochondrial cysteinome from oxidations in aging.
    Fengli Xu, Haipeng Huang, Kun Peng, Chongshu Jian, Hao Wu, Zhiwen Jing, Shan Qiu, Ying Chen, Keke Liu, Ling Fu, Yanru Wang, Jing Yang, Xiaotao Duan, Chu Wang, Heping Cheng, Xianhua Wang.
      Reactive thiols of proteinaceous cysteines are vital to cell biology by serving as sensor, effector and buffer of environmental redox fluctuations. Being the major source, as well as the prime target, of reactive oxygen species (ROS), mitochondria confront great challenges in preserving their thiol pool. Here we show that ROS modulator 1 (ROMO1), a small inner mitochondrial membrane protein, plays a role in protecting the mitochondrial cysteinome. ROMO1 is redox sensitive and reactive and overexpression can prevent deleterious oxidation of proteinaceous thiols. ROMO1 upregulation leads to a reductive shift of the mitochondrial cysteinome, exerting beneficial effects on mitochondria, such as promoting energy metabolism and Ca2+ uniport while inhibiting vicious membrane permeability transition. Importantly, ROMO1 overexpression reverses mitochondrial cysteinome oxidations in multiple organs and slows functional decline in aged male mice. These findings unravel a redox regulatory mechanism of the mitochondrial cysteinome and mark ROMO1 as a potential target for combating oxidative stress and improving healthspan.
    DOI:  https://doi.org/10.1038/s41467-025-60503-z
  10. Nat Cell Biol. 2025 Jun 03.
    Lactate dehydrogenase B facilitates disulfidptosis and exhaustion of tumour-infiltrating CD8+ T cells.
    Jie Wan, Jian-Hong Shi, Min Shi, Haiyan Huang, Zhen Zhang, Wenyan Li, Chenyue Guo, Rujuan Bao, Xiaoyan Yu, Qiaoqiao Han, Xian Du, Song Li, Youqiong Ye, Xingang Cui, Xia Li, Jing-Hua Li, Qiang Zou.
      The aberrant accumulation of intracellular disulfides promotes cancer cell disulfidptosis; however, how disulfide stress influences tumour-infiltrating CD8+ T cell function remains unknown. Here we demonstrate that lactate dehydrogenase B (LDHB) facilitates intratumoural CD8+ T cell disulfidptosis and exhaustion, leading to impaired antitumour immunity. SLC7A11-mediated cystine uptake by CD8+ T cells induces disulfidptosis, which plays critical roles in the development of exhausted CD8+ T cells. LDHB restricts glucose-6-phosphate dehydrogenase (G6PD) activity in exhausted CD8+ T cells by interacting with G6PD, causing NADPH depletion and consequently triggering disulfidptosis. Accordingly, the loss of LDHB in T cells prevents disulfidptosis-dependent CD8+ T cell exhaustion and improves antitumour immunity. Mechanistically, STAT3 directs LDHB expression to limit G6PD activity and mediate disulfidptosis in exhausted CD8+ T cells. Our results highlight the distinct roles of disulfidptosis and ferroptosis in driving CD8+ T cell exhaustion and suggest a potential therapeutic strategy to target LDHB in cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s41556-025-01673-2
  11. Science. 2025 Jun 05. 388(6751): 1026-1027
    The complex role of brain cilia in feeding control.
    Anushweta Asthana, Peter K Jackson.
      Variants in a ciliary receptor are associated with obesity.
    DOI:  https://doi.org/10.1126/science.ady6368
  12. Nature. 2025 Jun 04.
    Iron deficiency in pregnant mice causes XY embryos to develop with female characteristics.
    Shannon Dupont, Blanche Capel.
      
    Keywords:  Developmental biology; Epigenetics; Molecular biology
    DOI:  https://doi.org/10.1038/d41586-025-01456-7
  13. FASEB J. 2025 Jun 15. 39(11): e70665
    Inhibition of Cholesterol Synthesis in T Cells Protects the Liver Against Steatosis, Inflammation, and Oxidative Stress in Metabolic Dysfunction-Associated Steatohepatitis.
    Huizhen Lin, Jingwen Qi, Siwei Lin, Mengnan Lin, Zijie Chen, Yunhui Guo, Xin Zhang, Qi-Long Wang, Ting Cai, Wei Yang, Xiaojun Zheng.
      Metabolic dysfunction-associated steatohepatitis (MASH) is a manifestation of systemic metabolic disease defined by abnormal lipid metabolism and causes liver disease. Inflammation driven by immune cells has been linked to liver damage, fibrosis, and the progression of MASH. Here, single-cell transcriptome analysis disclosed the increasing hepatic infiltration of CD8+ T cells in a murine methionine- and choline-deficient (MCD) diet-induced MASH model. Simvastatin alleviated the progression of MCD-diet-induced MASH, accompanied by the decreased infiltration of T cells. Depletion of CD8+ T cells also improved MASH progression. It is widely recognized that cholesterol plays an indispensable role in tuning the activation and function of CD8+ T cells. We found that specific inhibition of cholesterol synthesis in T cells significantly reduced MCD-induced hepatic steatosis, damage, inflammation, and concurrently lowered the accumulation of T cells and macrophages in the liver. Mechanistic studies revealed that MCD-induced hepatic oxidative stress was reduced by inhibiting T-cell cholesterol metabolism. Simvastatin ameliorated MASH in mice, at least in part through inhibiting the infiltration and effector function of CD8+ T cells. Collectively, our findings provide compelling evidence that pharmacological modulation of T-cell cholesterol metabolism may represent a promising therapeutic approach in the treatment of MASH.
    Keywords:  T cells; cholesterol; metabolic dysfunction‐associated steatohepatitis; oxidative stress; simvastatin
    DOI:  https://doi.org/10.1096/fj.202500115R
  14. Nature. 2025 Jun 04.
    Structural insights into human Pol III transcription initiation in action.
    Qianmin Wang, Yulei Ren, Qianwei Jin, Xizi Chen, Yanhui Xu.
      RNA polymerase III (Pol III) transcribes highly demanded RNAs grouped into three types of classical promoters, including type 1 (5S rRNA), type 2 (tRNA) and type 3 (short non-coding RNAs, such as U6, 7SK and RNase H1) promoters1-7. While structures of the Pol III preinitiation complex (PIC)8-11 and elongation complex (EC)12-16 have been determined, the mechanism underlying the transition from initiation to elongation remains unclear. Here we reconstituted seven human Pol III transcribing complexes (TC4, TC5, TC6, TC8, TC10, TC12 and TC13) halted on U6 promoters with nascent RNAs of 4-13 nucleotides. Cryo-electron microscopy structures captured initially transcribing complexes (ITCs; TC4 and TC5) and ECs (TC6-13). Together with KMnO4 footprinting, the data reveal extensive modular rearrangements: the transcription bubble expands from PIC to TC5, followed by general transcription factor (GTF) dissociation and abrupt bubble collapse from TC5 to TC6, marking the ITC-EC transition. In TC5, SNAPc and TFIIIB remain bound to the promoter and Pol III, while the RNA-DNA hybrid adopts a tilted conformation with template DNA blocked by BRF2, a TFIIIB subunit. Hybrid forward translocation during ITC-EC transition triggers BRF2-finger retraction, GTF release and transcription-bubble collapse. Pol III then escapes the promoter while GTFs stay bound upstream, potentially enabling reinitiation. These findings reveal molecular insights into Pol III dynamics and reinitiation mechanisms on type 3 promoters of highly demanded small RNAs, with the earliest documented initiation-elongation transition for an RNA polymerase.
    DOI:  https://doi.org/10.1038/s41586-025-09093-w
  15. Nat Biotechnol. 2025 Jun 03.
    Base editors model mitochondrial disease.
    Patrick Buchholz, Jens Boch.
      
    DOI:  https://doi.org/10.1038/s41587-025-02706-9
  16. Nat Metab. 2025 Jun 03.
    Cysteine depletion triggers adipose tissue thermogenesis and weight loss.
    Aileen H Lee, Lucie Orliaguet, Yun-Hee Youm, Rae Maeda, Tamara Dlugos, Yuanjiu Lei, Daniel Coman, Irina Shchukina, Prabhakar Sairam Andhey, Steven R Smith, Eric Ravussin, Krisztian Stadler, Bandy Chen, Maxim N Artyomov, Fahmeed Hyder, Tamas L Horvath, Marc Schneeberger, Yuki Sugiura, Vishwa Deep Dixit.
      Caloric restriction and methionine restriction-driven enhanced lifespan and healthspan induces 'browning' of white adipose tissue, a metabolic response that increases heat production to defend core body temperature. However, how specific dietary amino acids control adipose thermogenesis is unknown. Here, we identified that weight loss induced by caloric restriction in humans reduces thiol-containing sulfur amino acid cysteine in white adipose tissue. Systemic cysteine depletion in mice causes lethal weight loss with increased fat utilization and browning of adipocytes that is rescued upon restoration of cysteine in diet. Mechanistically, cysteine-restriction-induced adipose browning and weight loss requires sympathetic nervous system-derived noradrenaline signalling via β3-adrenergic-receptors that is independent of FGF21 and UCP1. In obese mice, cysteine deprivation induced rapid adipose browning, increased energy expenditure leading to 30% weight loss and reversed metabolic inflammation. These findings establish that cysteine is essential for organismal metabolism as removal of cysteine in the host triggers adipose browning and rapid weight loss.
    DOI:  https://doi.org/10.1038/s42255-025-01297-8
  17. Nat Commun. 2025 Jun 03. 16(1): 5152
    Serotonergic neurons regulate the Drosophila vascular niche to control immune stress hematopoiesis.
    Xiaohui Liu, Marianne Montemurro, Nathalie Vanzo, Michèle Crozatier.
      In adult mammals, hematopoietic stem/progenitor cells reside in the bone marrow, in a specialized microenvironment called a "niche", which is composed of different cell types, including nerves. Although it is established that sympathetic nerves regulate hematopoiesis, little is known about the role of neural serotonin in bone marrow. The Drosophila hematopoietic organ, the lymph gland, is aligned along the aorta, which corresponds to the vascular niche. Here, we report that serotonin signaling in the vascular niche regulates the hematopoietic response to an immune challenge. The serotonin receptor 1B expressed in vascular niche cells, together with serotonin produced by neurons regulate the degradation of the extracellular matrix of the lymph gland and prevent its premature dispersal after an immune challenge. Serotonin signaling in aorta cells acts via JAK/STAT pathway activation. Our results provide novel insights into how vascular niche cells integrate neural information to regulate lymph gland immune stress hematopoiesis.
    DOI:  https://doi.org/10.1038/s41467-025-60493-y
  18. Nature. 2025 Jun 04.
    Male mice can grow female organs - if their mothers lack iron.
    Benjamin Thompson, Nick Petrić Howe.
      
    Keywords:  Climate change; Developmental biology; Sustainability
    DOI:  https://doi.org/10.1038/d41586-025-01762-0
  19. Science. 2025 Jun 05. 388(6751): eadl2116
    Is taurine an aging biomarker?
    Maria Emilia Fernandez, Michel Bernier, Nathan L Price, Simonetta Camandola, Miguel A Aon, Kelli Vaughan, Julie A Mattison, Joshua D Preston, Dean P Jones, Toshiko Tanaka, Qu Tian, Marta González-Freire, Luigi Ferrucci, Rafael de Cabo.
      Low circulating taurine concentrations have been proposed as a driver of the aging process. We found that circulating taurine concentrations increased or remained unchanged with age in three geographically distinct human cohorts as well as in nonhuman primates and mice when measured longitudinally (repeatedly in the same population) or cross-sectionally (sampling distinct populations at various ages). Moreover, considerable variability was observed in associations between taurine and age-related changes in health outcomes pertaining to gross motor function and energy homeostasis. Our results suggest that changes in circulating taurine are not a universal feature of aging and that its pleiotropic effects may be dependent on the temporal and physiological context of each individual.
    DOI:  https://doi.org/10.1126/science.adl2116
  20. Nat Med. 2025 Jun 05.
    The People-First Liver Charter.
    Jeffrey V Lazarus, Dana Ivancovsky Wajcman, Silvana Pannain, Paul N Brennan, Melina I Manolas, Peter Jepsen, Carla Treloar, Anish K Arora, Philippa C Matthews, Camila A Picchio, Trenton M White, Jason Grebely, Juan Vaz, Hannes Hagström, Kenneth H Rabin, Scott Isaacs, Rogério T Ribeiro, Michael Roden, Michael Betel, José Willemse, Luis Antonio Díaz, Alina M Allen, Naim Alkhouri, Jörn M Schattenberg, Dídac Mauricio, Mary E Rinella, Elisa Pose, Emmanuel A Tsochatzis, Michael Ninburg, Kenneth Cusi, William Alazawi, Ajay Duseja, Gema Frühbeck, Holly Lofton, Priya Jaisinghani, Fasiha Kanwal, Gamal Shiha, Shira Zelber-Sagi, Larry Holden, Marcela Villota-Rivas.
      
    DOI:  https://doi.org/10.1038/s41591-025-03759-8
  21. Nat Neurosci. 2025 Jun 02.
    Neuronal aging causes mislocalization of splicing proteins and unchecked cellular stress.
    Kevin Rhine, Rachel Li, Hema M Kopalle, Katherine Rothamel, Xuezhen Ge, Elle Epstein, Orel Mizrahi, Assael A Madrigal, Hsuan-Lin Her, Trent A Gomberg, Anita Hermann, Joshua L Schwartz, Amanda J Daniels, Uri Manor, John Ravits, Robert A J Signer, Eric J Bennett, Gene W Yeo.
      Aging is one of the most prominent risk factors for neurodegeneration, yet the molecular mechanisms underlying the deterioration of old neurons are mostly unknown. To efficiently study neurodegeneration in the context of aging, we transdifferentiated primary human fibroblasts from aged healthy donors directly into neurons, which retained their aging hallmarks, and we verified key findings in aged human and mouse brain tissue. Here we show that aged neurons are broadly depleted of RNA-binding proteins, especially spliceosome components. Intriguingly, splicing proteins-like the dementia- and ALS-associated protein TDP-43-mislocalize to the cytoplasm in aged neurons, which leads to widespread alternative splicing. Cytoplasmic spliceosome components are typically recruited to stress granules, but aged neurons suffer from chronic cellular stress that prevents this sequestration. We link chronic stress to the malfunctioning ubiquitylation machinery, poor HSP90α chaperone activity and the failure to respond to new stress events. Together, our data demonstrate that aging-linked deterioration of RNA biology is a key driver of poor resiliency in aged neurons.
    DOI:  https://doi.org/10.1038/s41593-025-01952-z
  22. Nat Med. 2025 Jun 04.
    Individual variations in glycemic responses to carbohydrates and underlying metabolic physiology.
    Yue Wu, Ben Ehlert, Ahmed A Metwally, Dalia Perelman, Heyjun Park, Andrew Wallace Brooks, Fahim Abbasi, Basil Michael, Alessandra Celli, Caroline Bejikian, Ekrem Ayhan, Yingzhou Lu, Samuel M Lancaster, Daniel Hornburg, Lucia Ramirez, David Bogumil, Sarah Pollock, Frank Wong, Denver Bradley, Georg Gutjahr, Ekanath Srihari Rangan, Tao Wang, Lettie McGuire, P Venkat Rangan, Helge Ræder, Zohar Shipony, Doron Lipson, Tracey McLaughlin, Michael P Snyder.
      Elevated postprandial glycemic responses (PPGRs) are associated with type 2 diabetes and cardiovascular disease. PPGRs to the same foods have been shown to vary between individuals, but systematic characterization of the underlying physiologic and molecular basis is lacking. We measured PPGRs using continuous glucose monitoring in 55 well-phenotyped participants challenged with seven different standard carbohydrate meals administered in replicate. We also examined whether preloading a rice meal with fiber, protein or fat ('mitigators') altered PPGRs. We performed gold-standard metabolic tests and multi-omics profiling to examine the physiologic and molecular basis for interindividual PPGR differences. Overall, rice was the most glucose-elevating carbohydrate meal, but there was considerable interindividual variability. Individuals with the highest PPGR to potatoes (potato-spikers) were more insulin resistant and had lower beta cell function, whereas grape-spikers were more insulin sensitive. Rice-spikers were more likely to be Asian individuals, and bread-spikers had higher blood pressure. Mitigators were less effective in reducing PPGRs in insulin-resistant as compared to insulin-sensitive participants. Multi-omics signatures of PPGR and metabolic phenotypes were discovered, including insulin-resistance-associated triglycerides, hypertension-associated metabolites and PPGR-associated microbiome pathways. These results demonstrate interindividual variability in PPGRs to carbohydrate meals and mitigators and their association with metabolic and molecular profiles.
    DOI:  https://doi.org/10.1038/s41591-025-03719-2
  23. Diabetologia. 2025 Jun 02.
    Increased inflammation as well as decreased endoplasmic reticulum stress and translation differentiate pancreatic islets from donors with pre-symptomatic stage 1 type 1 diabetes and non-diabetic donors.
    Adam C Swensen, Paul D Piehowski, Jing Chen, X'avia Y Chan, Shane S Kelly, Vladislav A Petyuk, Ronald J Moore, Lith Nasif, Elizabeth A Butterworth, Mark A Atkinson, Rohit N Kulkarni, Martha Campbell-Thompson, Clayton E Mathews, Wei-Jun Qian.
       AIMS/HYPOTHESIS: Progression to type 1 diabetes is associated with genetic factors, the presence of autoantibodies and a decline in beta cell insulin secretion in response to glucose. Very little is known regarding the molecular changes that occur in human insulin-secreting beta cells prior to the onset of type 1 diabetes. Herein, we applied an unbiased proteomics approach to identify changes in proteins and potential mechanisms of islet dysfunction in islet-autoantibody-positive organ donors with pre-symptomatic stage 1 type 1 diabetes (HbA1c ≤42 mmol/mol [6.0%]). We aimed to identify pathways in islets that are indicative of beta cell dysfunction.
    METHODS: Multiple islet sections were collected through laser microdissection of frozen pancreatic tissues from organ donors positive for single or multiple islet autoantibodies (AAb+, n=5), and age (±2 years)- and sex-matched non-diabetic (ND) control donors ( n=5) obtained from the Network for Pancreatic Organ donors with Diabetes (nPOD). Islet sections were subjected to MS-based proteomics and analysed with label-free quantification followed by pathway and functional annotations.
    RESULTS: Analyses resulted in ~4500 proteins identified with low false discovery rate (<1%), with 2165 proteins reliably quantified in every islet sample. We observed large inter-donor variations that presented a challenge for statistical analysis of proteome changes between donor groups. We therefore focused on only the donors with stage 1 type 1 diabetes who were positive for multiple autoantibodies (mAAb+, n=3) and genetic risk compared with their matched ND controls (n=3) for the final statistical analysis. Approximately 10% of the proteins (n=202) were significantly different (unadjusted p<0.025, q<0.15) for mAAb+ vs ND donor islets. The significant alterations clustered around major functions for upregulation in the immune response and glycolysis, and downregulation in endoplasmic reticulum (ER) stress response as well as protein translation and synthesis. The observed proteome changes were further supported by several independent published datasets, including a proteomics dataset from in vitro proinflammatory cytokine-treated human islets and single-cell RNA-seq datasets from AAb+ individuals.
    CONCLUSIONS/INTERPRETATION: In situ human islet proteome alterations in stage 1 type 1 diabetes centred around several major functional categories, including an expected increase in immune response genes (elevated antigen presentation/HLA), with decreases in protein synthesis and ER stress response, as well as compensatory metabolic response. The dataset serves as a proteomics resource for future studies on beta cell changes during type 1 diabetes progression and pathogenesis.
    DATA AVAILABILITY: The LC-MS raw datasets that support the findings of this study have been deposited in the online repository: MassIVE ( https://massive.ucsd.edu/ProteoSAFe/static/massive.jsp ) with accession no. MSV000090212.
    Keywords:  Autoantibody-positive; Beta cells; Human islets; Islet proteome; Laser microdissection; Mass spectrometry; NPOD; Prediabetes; Proteomics
    DOI:  https://doi.org/10.1007/s00125-025-06417-3
  24. J Clin Invest. 2025 Jun 03. pii: e184653. [Epub ahead of print]
    Panose prevents acute-on-chronic liver failure by reducing bacterial infection in mice.
    Jiaxin Li, Shihao Xie, Meiling Chen, Changze Hong, Yuqi Chen, Fengyuan Lyu, Niexin Tang, Tianqi Chen, Lingyan Zhao, Weihao Zou, Hongjuan Peng, Jingna Bao, Peng Gu, Bernd Schnabl, Jinjun Chen, Peng Chen.
      Acute-on-chronic liver failure (ACLF) is a leading cause of global liver-related mortality. Bacterial infection, especially in patients with decompensated cirrhosis (DC), commonly triggers ACLF and is difficult to treat with antibiotics. Therefore, finding alternative strategies for preventing and managing bacterial infection is an urgent priority. Here, we observed that infected DC patients and ACLF mice exhibited lower fecal panose levels than uninfected controls. Megamonas funiformis (M. funiformis), with 4α-glucanosyltransferase (4αGT) as a key enzyme for panose production, was identified as a potential panose producer. Animal experiments demonstrated that panose efficiently reduced liver injury and extended survival in ACLF mice by mitigating bacterial infection. Further results revealed that panose enhanced resistance to bacterial infection by inhibiting oxidative stress-induced gut barrier disruption, thereby limiting bacterial dissemination. Mechanistically, panose interacted with the solute carrier family 7 member 11 (SLC7A11, also known as xCT) protein to boost antioxidant glutathione (GSH) levels in intestinal epithelial cells. These findings highlight panose's potential in preventing bacterial infection, offering a valuable insight into mitigating ACLF progression.
    Keywords:  Bacterial infections; Hepatology; Metabolism; Microbiology; Tight junctions
    DOI:  https://doi.org/10.1172/JCI184653
  25. J Clin Invest. 2025 Jun 02. pii: e184313. [Epub ahead of print]135(11):
    Assessing the health of the gut microbial organ: why and how?
    Orlando DeLeon, Eugene B Chang.
      
    DOI:  https://doi.org/10.1172/JCI184313
  26. Cell Metab. 2025 Jun 03. pii: S1550-4131(25)00255-4. [Epub ahead of print]37(6): 1252-1254
    Metabolic switches in cell death regulation.
    Lorenzo Galluzzi.
      The death of mammalian cells is generally regulated by a complex interplay amongst distinct molecular machineries that ultimately determines the kinetic and immunological consequences of the process. Recent data from Song et al. delineate a new metabolic circuitry through which apoptotic signals may actively suppress cell death via ferroptosis.
    DOI:  https://doi.org/10.1016/j.cmet.2025.04.017
  27. Nat Commun. 2025 Jun 04. 16(1): 5206
    Brown adipose tissue secretes OLFM4 to coordinate sensory and sympathetic innervation via Schwann cells.
    Mingqiang Lai, Wu Zhou, Wenchong Zou, Lianlian Qiu, Zhaoyu Liang, Wanyi Chen, Yiqing Wang, Bin Guo, Chaoran Zhao, Sheng Zhang, Pinglin Lai, Le Hu, Xiaolin Liu, Yu Jiang, Yinghua Chen, Min-Jun Huang, Xiaochun Bai, Zhipeng Zou.
      Non-shivering thermogenesis of brown adipose tissue (BAT) is tightly controlled by neural innervation. However, the underlying mechanism remains unclear. Here, we reveal that BAT regulates its own thermoadaptive innervation by crosstalk with Schwann cells (SCs). Loss of Olfm4 (encoding Olfactomedin-4), a risk gene in human obesity, causes BAT dysfunction and reduces whole-body thermogenesis, predisposing to obesity in mice. Mechanistically, BAT-derived OLFM4 traps Noggin, an endogenous inhibitor of BMPs, liberating BMP7-BMPR1B signaling to promote SC differentiation. Conversely, Olfm4 loss reduced BMP7 signaling in mature SCs, leading to MEK/ERK-dependent dedifferentiation and dysfunction, ultimately impairing both sensory and sympathetic innervation. Thermoneutrality exposure reduces Olfm4 expression in BAT, resulting in a similar phenotype. MEK/ERK inhibition, ERK1 depletion, or cold exposure reverses this SC dedifferentiation, enhancing resistance to obesity. These findings suggest that this neurotrophic BAT-SC crosstalk controls thermoadaptive BAT innervation. Reactivating OLFM4 signaling may be a promising therapeutic strategy for obesity and related metabolic diseases.
    DOI:  https://doi.org/10.1038/s41467-025-60474-1
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