bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2025–08–31
35 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. CRISPR screens identify STUB1 as an inhibitor of cytokine signaling in CD8+ T cells.
  2. Resolving fibrosis by stimulating HSC-dependent extracellular matrix degradation.
  3. Dietary saturated fatty acids promote lung myeloid cell inflammasome activation and IL-1β-mediated inflammation in mice and humans.
  4. Discovery of a multi-chaperone condensate in the endoplasmic reticulum.
  5. Helicobacter hepaticus promotes hepatic steatosis through CdtB-induced mitochondrial stress and lipid metabolism reprogramming.
  6. Genetics-nutrition interactions control diurnal enhancer-promoter dynamics and liver lipid metabolism.
  7. Visualizing lipid transport in cells.
  8. Mitochondria transfer.
  9. Spatial isotope deep tracing deciphers inter-tissue metabolic crosstalk.
  10. An abiding mystery of the French Revolution is solved - by epidemiology.
  11. GraphVelo allows for accurate inference of multimodal velocities and molecular mechanisms for single cells.
  12. Single-cell DNA methylome and 3D genome atlas of human subcutaneous adipose tissue.
  13. IFN-β and ARTS deficiency promote the generation of hyper-efferocytic Ly6C+ macrophages in resolving inflammation in male mice.
  14. How did life get multicellular? Five simple organisms could have the answer.
  15. Thymic epithelial cells amplify epigenetic noise to promote immune tolerance.
  16. Splicing QTL mapping in stimulated macrophages associates low-usage splice junctions with immune-mediated disease risk.
  17. Proton-activated chloride channel governs phagosome-mediated antibacterial immunity in peritoneal macrophages.
  18. A closer look at how cells sense dietary nutrients.
  19. A regulator of amino acid sensing links lipid peroxidation and lipid droplet-dependent antioxidant response.
  20. Crotonylation of IDH1 alleviates MASLD progression by enhancing the TCA cycle.
  21. Mitochondrial ROS drive foam cell formation via STAT5 signaling in atherosclerosis.
  22. Ultra-processed diets promote excess calorie consumption.
  23. NSUN2 facilitates DICER cleavage of DNA damage-associated R-loops to promote repair.
  24. Gene expression QTL mapping in stimulated iPSC-derived macrophages provides insights into common complex diseases.
  25. Multi-omic identification of perineurial hyperplasia and lipid-associated nerve macrophages in human polyneuropathies.
  26. A chaperone-proteasome-based fragmentation machinery is essential for aggrephagy.
  27. Seeding of visceral adipose tissue with perinatally generated regulatory T cells shapes the metabolic tenor in mice.
  28. IL6 genetic perturbation mimicking IL-6 inhibition is associated with lower cardiometabolic risk.
  29. Interplay of genetic predisposition, plasma metabolome and Mediterranean diet in dementia risk and cognitive function.
  30. Investigating metabolic changes in single embryos during early development in Drosophila.
  31. Quantitative imaging of lipid transport in mammalian cells.
  32. CX3CR1+ macrophages interact with HSCs to promote HCC through CD8+ T-cell suppression.
  33. ALS/FTD-linked TBK1 deficiency in microglia induces an aged-like microglial signature and drives social recognition deficits in mice.
  34. Region-specific gene expression and sex inform about disease susceptibility in the aorta.
  35. Viral spread: how rumours surged in revolutionary France.
  1. Nat Immunol. 2025 Sep;26(9): 1436-1437
    CRISPR screens identify STUB1 as an inhibitor of cytokine signaling in CD8+ T cells.
      
    DOI:  https://doi.org/10.1038/s41590-025-02247-y
  2. Sci Transl Med. 2025 Aug 27. 17(813): eads9470
    Resolving fibrosis by stimulating HSC-dependent extracellular matrix degradation.
    Sachin Sharma, Vijaya Prathigudupu, Carson Cable, Lia R Serrano, Srilaxmi Nerella, Alina Chen, Ghmkin Hassan, Johnathon Lakins, Carlos Lizama Valenzuela, Tatsuya Tsukui, Roopa Ramamoorthi, Jae-Jun Kim, Holger Willenbring, Aras N Mattis, Regan F Volk, Balyn W Zaro, Joshua J Coon, Richard Beresis, William F DeGrado, Valerie M Weaver, Stephanie A Christenson, Hyunil Jo, Jennifer Y Chen.
      Tissue fibrosis arises from a critical imbalance between the production and breakdown of extracellular matrix (ECM) components. Whereas current strategies predominantly focus on curbing ECM production, the possibility of promoting ECM degradation to resolve fibrosis remains largely untapped. The role of hepatic stellate cells (HSCs) in ECM degradation is an intriguing area for investigation. We previously demonstrated that inhibiting acid ceramidase (aCDase) increases ceramide in HSCs to ameliorate hepatic fibrosis. Here, we uncover a key signaling pathway that promotes ECM degradation in primary human HSCs, which is dependent upon the activation of protein kinase Cα (PKCα) and the induction of matrix metalloproteinase 1 (MMP-1) through extracellular signal-regulated kinase 1/2 (ERK1/2). Genetic reduction and pharmacological inhibition with a small molecule reduced aCDase activity, leading to increased collagen degradation and hepatic fibrosis resolution in the carbon tetrachloride (CCl4) and fructose, palmitate, cholesterol, and trans-fat (FPC) mouse models. Consistently, ceramide signaling correlated with ECM remodeling and degradation in patients with metabolic dysfunction-associated steatotic liver disease. The findings show that ceramide regulates ECM degradation and establish aCDase as a target for therapeutic regression of fibrosis.
    DOI:  https://doi.org/10.1126/scitranslmed.ads9470
  3. Sci Transl Med. 2025 Aug 27. 17(813): eadp5653
    Dietary saturated fatty acids promote lung myeloid cell inflammasome activation and IL-1β-mediated inflammation in mice and humans.
    Sam J McCright, Olivia Harding, Julia Chini, Nicole DeMarco, Li-Yin Hung, Christopher F Pastore, Wenyun Lu, Joshua Rabinowitz, Jorge Henao-Mejia, De'Broski R Herbert, Lisa R Young, David A Hill.
      Resident tissue macrophages and monocytes (RTMs) integrate local and systemic signals to coordinate immune cell function at homeostasis and in response to inflammatory stimuli. Obesity-associated metabolic dysfunction drives the development of RTM populations that contribute to disease states in multiple tissues. However, the contribution of specific dietary components to innate immune cell activation and function, as opposed to the direct effects of obesity, is largely unknown. Here, we studied the mechanisms by which high-fat (HF) diets shape lung RTM phenotype and function at steady state and influence responses to inflammatory insults. We found that, during HF diet feeding, lung RTMs accumulate saturated long-chain fatty acids, specifically stearic acid (SA), and demonstrate features of NLRP3 inflammasome priming and activation. In vivo, increased dietary SA was sufficient to cause neutrophil-predominant lung inflammation in the steady state and exacerbate a model of innate airway inflammation, whereas increased dietary oleic acid, the monounsaturated counterpart of SA, was sufficient to reduce inflammasome activation in the steady state and attenuate airway inflammation. Depletion of interleukin-1β (IL-1β) or pharmacologic inhibition of the endonuclease inositol requiring enzyme 1α (IRE1α) protected against SA-induced exacerbated lung inflammation. Last, we identified a population of lung monocytes with hallmarks of HF diet-induced RTM activation that were present in samples from obese humans with asthma. Together, these results identify a class of dietary lipids that regulate lung RTM phenotype and function in the steady state and modulate the severity of inflammation in the lung.
    DOI:  https://doi.org/10.1126/scitranslmed.adp5653
  4. Nat Cell Biol. 2025 Aug 20.
    Discovery of a multi-chaperone condensate in the endoplasmic reticulum.
      
    DOI:  https://doi.org/10.1038/s41556-025-01731-9
  5. Nat Commun. 2025 Aug 26. 16(1): 7954
    Helicobacter hepaticus promotes hepatic steatosis through CdtB-induced mitochondrial stress and lipid metabolism reprogramming.
    Shanhao Jin, Liqi Zhu, Ruoyu Bao, Linghan Yang, Tinglong Zhuang, Liyou Lian, Tao Wang, Jun Yin, Shilei Zhang, Lei Zhou, Minghua Zheng, Quan Zhang.
      Host-pathogen interaction influences many non-infectious diseases, including metabolic diseases. Helicobacter hepaticus (H. hepaticus) has been found in some metabolic dysfunction-associated steatotic liver disease (MASLD) patients, however, the causal link and underlying mechanisms remain unclear. Here we report that H. hepaticus infection or overexpression of CdtB of H. hepaticus induces lipid deposition in hepatocytes, both in vivo and in vitro. Furthermore, we identify that CdtB translocates to mitochondria with the help of Hsp90, interacts with ATP5A1, reduces mitochondrial respiratory complex V activity, damages mitochondria, and disrupts lipid metabolism. Mechanistically, CdtB-induced lipogenesis depends on the CdtB-mitochondrial ROS-mTORC1-SREBP1 axis and CdtB-mediated NONO expression to enhance nuclear localization of SREBP1 that promote the de novo fatty acid synthesis in the hepatocytes. Neutralization of CdtB significantly alleviates hepatic lipidosis in mice upon H. hepaticus infection. Furthermore, the nucleic acid of H. hepaticus has been detected in the liver tissues of some patients with MASLD, which suggests a certain correlation between liver infection with H. hepaticus and the occurrence and progression of MASLD. Our findings highlight the critical role of CdtB in the pathogenesis of H. hepaticus infection-induced hepatic lipidosis and its potential as a therapeutic target.
    DOI:  https://doi.org/10.1038/s41467-025-63351-z
  6. Cell Metab. 2025 Aug 19. pii: S1550-4131(25)00356-0. [Epub ahead of print]
    Genetics-nutrition interactions control diurnal enhancer-promoter dynamics and liver lipid metabolism.
    Dishu Zhou, Ying Chen, Panpan Liu, Kun Zhu, Juliet Holder-Haynes, S Julie-Ann Lloyd, Cam Mong La, Inna I Astapova, Seunghee Choa, Ying Xiong, Hosung Bae, Marlene Aguilar, Hongyuan Yang, Yu A An, Zheng Sun, Mark A Herman, Xia Gao, Liming Pei, Cholsoon Jang, Joshua D Rabinowitz, Samer G Mattar, Yongyou Zhang, Dongyin Guan.
      The circadian clock controls 24-h rhythmic processes. However, how genetic variations outside clock genes impact peripheral diurnal rhythms remains largely unknown. Here, we find that genetic variation contributes to different diurnal patterns of hepatic gene expression in both humans and mice. Nutritional challenges alter the rhythmicity of gene expression in mouse liver in a strain-specific manner. Remarkably, genetics and nutrition interdependently control more than 80% of rhythmic gene and enhancer-promoter interactions (E-PIs), with a noncanonical clock regulator, estrogen-related receptor gamma (ESRRγ), emerging as a top transcription factor during motif mining. Knockout of Esrrγ abolishes strain-specific metabolic processes in response to diet in mice, while single-nucleotide polymorphisms (SNPs) associated with rhythmic gene expression are enriched in E-PIs in steatotic human livers and correlate with lipid metabolism traits. These findings reveal a previously underappreciated temporal aspect of genetics-environment interaction in regulating lipid metabolic traits, with implications for individual variations in obesity-associated disease susceptibility and personalized chronotherapy.
    Keywords:  3D enhancer-promoter interaction; diurnal rhythm; genetic variation; human metabolic traits; metabolic disorders
    DOI:  https://doi.org/10.1016/j.cmet.2025.07.010
  7. Nature. 2025 Aug 20.
    Visualizing lipid transport in cells.
      
    Keywords:  Biological techniques; Cell biology; Imaging
    DOI:  https://doi.org/10.1038/d41586-025-02603-w
  8. Nat Metab. 2025 Aug 27.
    Mitochondria transfer.
    Navdeep S Chandel, Marni J Falk, Janine H Santos, Jonathan R Brestoff, Ana V Lechuga-Vieco, Yasemin S Sancak, Quan Chen, Alvaro A Elorza, Rubén Quintana-Cabrera.
      
    DOI:  https://doi.org/10.1038/s42255-025-01364-0
  9. Nat Commun. 2025 Aug 26. 16(1): 7934
    Spatial isotope deep tracing deciphers inter-tissue metabolic crosstalk.
    Xinzhu Li, Ying Zhu, Ting Li, Xinyi Tu, Shiyu Zhu, Lingzhi Wang, Fei Li, Chenglong Sun, Xin Li, Haiyi Zhao, Tang Tang, Qingce Zang, Ruiping Zhang, Zeper Abliz.
      Organs collaborate to maintain metabolic homeostasis in mammals. Spatial metabolomics makes strides in profiling the metabolic landscape, yet can not directly inspect the metabolic crosstalk between tissues. Here, we introduce an approach to comprehensively trace the metabolic fate of 13C-nutrients within the body and present a robust computational tool, MSITracer, to deep-probe metabolic activity in a spatial manner. By discerning spatial distribution differences between isotopically labeled metabolites from ambient mass spectrometry imaging-based isotope tracing data, this approach empowers us to characterize fatty acid metabolic crosstalk between the liver and heart, as well as glutamine metabolic exchange across the kidney, liver, and brain. Moreover, we disclose that tumor burden significantly influences the host's hexosamine biosynthesis pathway, and that the glucose-derived glutamine released from the lung as a potential source for tumor glutamate synthesis. The developed approach facilitates the systematic characterization of metabolic activity in situ and the interpretation of tissue metabolic communications in living organisms.
    DOI:  https://doi.org/10.1038/s41467-025-63243-2
  10. Nature. 2025 Aug 27.
    An abiding mystery of the French Revolution is solved - by epidemiology.
    Mariana Lenharo.
      
    Keywords:  Epidemiology; History; Sociology
    DOI:  https://doi.org/10.1038/d41586-025-02739-9
  11. Nat Commun. 2025 Aug 22. 16(1): 7831
    GraphVelo allows for accurate inference of multimodal velocities and molecular mechanisms for single cells.
    Yuhao Chen, Yan Zhang, Jiaqi Gan, Ke Ni, Ming Chen, Ivet Bahar, Jianhua Xing.
      RNA velocities and generalizations emerge as powerful approaches for extracting time-resolved information from high-throughput snapshot single-cell data. Yet, several inherent limitations restrict applying the approaches to genes not suitable for RNA velocity inference due to complex transcriptional dynamics, low expression, or lacking splicing dynamics, or data of non-transcriptomic modality. Here, we present GraphVelo, a graph-based machine learning procedure that uses as input the RNA velocities inferred from existing methods and infers velocity vectors lying in the tangent space of the low-dimensional manifold formed by the single cell data. GraphVelo preserves vector magnitude and direction information during transformations across different data representations. Tests on synthetic and experimental single-cell data, including viral-host interactome, multi-omics, and spatial genomics datasets demonstrate that GraphVelo, together with downstream generalized dynamo analyses, extends RNA velocities to multi-modal data and reveals quantitative nonlinear regulation relations between genes, virus, and host cells, and different layers of gene regulation.
    DOI:  https://doi.org/10.1038/s41467-025-62784-w
  12. Nat Genet. 2025 Aug 20.
    Single-cell DNA methylome and 3D genome atlas of human subcutaneous adipose tissue.
    Zeyuan Johnson Chen, Sankha Subhra Das, Asha Kar, Seung Hyuk T Lee, Kevin D Abuhanna, Marcus Alvarez, Mihir G Sukhatme, Zitian Wang, Kyla Z Gelev, Matthew G Heffel, Yi Zhang, Oren Avram, Elior Rahmani, Sriram Sankararaman, Markku Laakso, Sini Heinonen, Hilkka Peltoniemi, Eran Halperin, Kirsi H Pietiläinen, Chongyuan Luo, Päivi Pajukanta.
      The cell-type-level epigenomic landscape of human subcutaneous adipose tissue (SAT) is not well characterized. Here, we elucidate the epigenomic landscape across SAT cell types using snm3C-seq. We find that SAT CG methylation (mCG) displays pronounced hypermethylation in myeloid cells and hypomethylation in adipocytes and adipose stem and progenitor cells, driving nearly half of the 705,063 differentially methylated regions (DMRs). Moreover, TET1 and DNMT3A are identified as plausible regulators of the cell-type-level mCG profiles. Both global mCG profiles and chromosomal compartmentalization reflect SAT cell-type lineage. Notably, adipocytes display more short-range chromosomal interactions, forming complex local 3D genomic structures that regulate transcriptional functions, including adipogenesis. Furthermore, adipocyte DMRs and A compartments are enriched for abdominal obesity genome-wide association study (GWAS) variants and polygenic risk, while myeloid A compartments are enriched for inflammation. Together, we characterize the SAT single-cell-level epigenomic landscape and link GWAS variants and partitioned polygenic risk of abdominal obesity and inflammation to the SAT epigenome.
    DOI:  https://doi.org/10.1038/s41588-025-02300-4
  13. Commun Biol. 2025 Aug 23. 8(1): 1269
    IFN-β and ARTS deficiency promote the generation of hyper-efferocytic Ly6C+ macrophages in resolving inflammation in male mice.
    Orly Zeituni-Timor, Soaad Soboh, Ahmad Zaid, Hiba Yaseen, Senthil Kumaran Satyanarayanan, Maha Abu Zeid, Esther Silberberg, Priya Goswami, Sagie Schif-Zuck, Sarit Larisch, Amiram Ariel.
      During the resolution of inflammation, Ly6C+F4/80- monocytes differentiate to Ly6C-F4/80+ macrophages that exert apoptotic cell engulfment (efferocytosis) properties and consequently convert to interferon (IFN)-β-producing macrophages. Here, we report that exposure to IFN-β, or transforming growth factor (TGF)-β, or a deficiency in the pro-apoptotic protein ARTS, results in the conversion of mature macrophages to an Ly6C+F4/80+CCR2+ phenotype in vivo and ex vivo. Deficiency in ARTS or caspase inhibition results in enhanced conversion of macrophages to the Ly6C+ phenotype. Moreover, IFN-β-triggered Ly6C+ macrophages are hyper-efferocytic and express higher levels of the efferocytic receptor CD36. Inhibition of CD36 ligation results in complete abrogation of efferocytosis ex vivo in both Ly6C+ and Ly6C- macrophages. Notably, IFN-β also promotes the emergence of Ly6C+ macrophages during the resolution of liver fibrosis, while transcriptomic analysis further links this rejuvenated phenotype to macrophage subsets found in human inflammatory liver disease. Altogether, our findings indicate IFN-β promotes macrophage conversion to a distinct hyper-efferocytic phenotype that is limited by ARTS and apoptosis during the resolution of inflammation.
    DOI:  https://doi.org/10.1038/s42003-025-08707-3
  14. Nature. 2025 Aug;644(8078): 856-859
    How did life get multicellular? Five simple organisms could have the answer.
    Alla Katsnelson.
      
    Keywords:  Cell biology; Evolution; Genetics; Microbiology; Molecular biology
    DOI:  https://doi.org/10.1038/d41586-025-02635-2
  15. Nature. 2025 Aug 20.
    Thymic epithelial cells amplify epigenetic noise to promote immune tolerance.
    Noah Gamble, Jason A Caldwell, Joshua McKeever, Caroline Kaiser, Alexandra Bradu, Peyton J Dooley, Sandy Klemm, William J Greenleaf, Narutoshi Hibino, Aaron R Dinner, Andrew S Koh.
      Cellular plasticity is a principal feature of vertebrate adaptation, tissue repair and tumorigenesis1,2. However, the mechanisms that regulate the stability of somatic cell fates remain unclear. Here, we use the somatic plasticity of thymic epithelial cells, which facilitates the selection of a self-discriminating T cell repertoire3, as a physiological model system to show that fluctuations in background chromatin accessibility in nucleosome-dense regions are amplified during thymic epithelial maturation for the ectopic expression of genes restricted to other specialized cell types. This chromatin destabilization was not dependent on AIRE-induced transcription but was preceded by repression of the tumour suppressor p53. Augmenting p53 activity indirectly stabilized chromatin, inhibited ectopic transcription, limited cellular plasticity and caused multi-organ autoimmunity. Genomic regions with heightened chromatin accessibility noise were selectively enriched for nucleosome-destabilizing polymeric AT tracts and were associated with elevated baseline DNA damage and transcriptional initiation. Taken together, our findings define molecular levers that modulate cell fate integrity and are used by thymic epithelial cells for immunological tolerance.
    DOI:  https://doi.org/10.1038/s41586-025-09424-x
  16. Nat Commun. 2025 Aug 27. 16(1): 7205
    Splicing QTL mapping in stimulated macrophages associates low-usage splice junctions with immune-mediated disease risk.
    Omar El Garwany, Nikolaos I Panousis, Andrew Knights, Natsuhiko Kumasaka, Maria Imaz, Lorena Boquete Vilarino, Anthi Tsingene, Alex Tokolyi, Cristina Cotobal Martin, Tobi Alegbe, Monika Krzak, Tim Raine, Alice Barnett, Celine Gomez, Daniel J Gaffney, Carl A Anderson.
      The majority of immune-mediated disease (IMD) risk loci are located in non-coding regions of the genome, making it difficult to decipher their functional effects in relevant physiological contexts. To assess the extent to which alternative splicing contributes to IMD risk, we mapped genetic variants associated with alternative splicing (splicing quantitative trait loci or sQTL) in macrophages exposed to a wide range of environmental stimuli. We found that genes involved in innate immune response pathways undergo extensive differential splicing in response to stimulation and detected significant sQTL effects for over 5734 genes across all stimulation conditions. We colocalised sQTL signals for over 700 genes with IMD-associated risk loci from 22 IMDs with high confidence (PP4 ≥ 0.75). Approximately half of the colocalisations implicate lowly-used splice junctions (mean usage ratio <0.1). Finally, we demonstrate how an inflammatory bowel disease (IBD) risk allele increases the usage of a lowly-used isoform of PTPN2, a negative regulator of inflammation. Together, our findings highlight the role alternative splicing plays in IMD risk, and suggest that lowly-used splicing events significantly contribute to complex disease risk.
    DOI:  https://doi.org/10.1038/s41467-025-61669-2
  17. J Exp Med. 2025 Nov 03. pii: e20250312. [Epub ahead of print]222(11):
    Proton-activated chloride channel governs phagosome-mediated antibacterial immunity in peritoneal macrophages.
    Henry Yi Cheng, Jiachen Chu, Nathachit Limjunyawong, Jianan Chen, Yingzhi Ye, Kevin Hong Chen, Nicholas Koylass, Shuying Sun, Xinzhong Dong, Zhaozhu Qiu.
      The success of phagosome degradation relies on the ability of phagocytes to regulate the maturation of phagosomes. However, its underlying molecular mechanisms remain poorly understood. Here, we identify the proton-activated chloride (PAC) channel as a key negative regulator of phagosome maturation. PAC deletion enhanced phagosomal acidification and protease activities, leading to augmented bacterial killing in large peritoneal macrophages (LPMs) upon Escherichia coli infection in mice. Surprisingly, phagosome degradation also stimulated STING-IRF3-IFN responses and inflammasome activation in LPMs, both of which are enhanced upon PAC deletion. The increased inflammasome activation induced the release of cleaved gasdermin D, which localized to the surface of bacteria in the peritoneum and further contributed to their killing. Finally, enhanced bacterial clearance by PAC-deficient LPMs reduced proinflammatory immune cell infiltration and peritoneal inflammation, resulting in improved survival in mice. Our study thus provides new insights into the molecular mechanism of phagosome maturation and the dynamics of host defense response following phagosome-mediated bacterial degradation in peritoneal macrophages.
    DOI:  https://doi.org/10.1084/jem.20250312
  18. Nature. 2025 Aug 27.
    A closer look at how cells sense dietary nutrients.
      
    Keywords:  Cell biology; Metabolism; Structural biology
    DOI:  https://doi.org/10.1038/d41586-025-02694-5
  19. Mol Cell. 2025 Aug 19. pii: S1097-2765(25)00659-8. [Epub ahead of print]
    A regulator of amino acid sensing links lipid peroxidation and lipid droplet-dependent antioxidant response.
    Jinhua Li, Yansong Zhang, Jingyu Peng, Wei Yang, Yanzhe Pan, Ying Xu, Jiayi Yao, Siyuan Lin, Yizhi Li, Xinran Gu, Wei Dong, Xiang Yu, Ming Ge, Min Liu, Alan Jian Zhu.
      Recent studies highlight the antioxidant role of lipid droplets (LDs) in shielding unsaturated lipids from peroxidation. While LDs accumulate during oxidative stress, the underlying mechanism remains unclear. Our previous research revealed that intracellular amino acids directly bind to and activate the E3 ubiquitin ligase Ubr1 to degrade Plin2, an LD protein inhibiting lipolysis. Here, we unexpectedly find that Ubr1's ability to bind to amino acids is inhibited during oxidative stress. Mechanistically, oxidative stress-induced lipid peroxidation blocks the activity of Hsc70-4, an ATPase that maintains the amino-acid-binding ability of Ubr1. 4-hydroxynonenal, a reactive product of lipid peroxidation, covalently modifies and inactivates Hsc70-4, leading to Ubr1 inactivation, Plin2 stabilization, and LD accumulation. Increased LDs minimize lipid peroxidation, thus protecting cells from oxidative damage and cell death. Together, we identify a regulator of amino acid sensing with redox-dependent activity, bridging the gap in understanding how lipid peroxidation stimulates LD-dependent antioxidant responses.
    Keywords:  4-hydroxynonenal; HSPA8; Hsc70-4; Plin2; Ubr1; amino acid sensing; antioxidant response; lipid droplet; lipid peroxidation
    DOI:  https://doi.org/10.1016/j.molcel.2025.08.009
  20. Nat Commun. 2025 Aug 26. 16(1): 7961
    Crotonylation of IDH1 alleviates MASLD progression by enhancing the TCA cycle.
    Shanshan Liu, Yu Ji, Luyang Wei, Yiqiao Zhang, Linghang Zeng, Yiyang Min, Danyang Yin, Kun Liu, Chengjian Guan, Shumeng Liu, Huajing Yu, Zhongtao Zhang.
      Metabolic dysfunction-associated steatotic liver disease (MASLD), potentially ameliorated by bariatric-metabolic surgery, remains a global health concern in the absence of approved drugs. Protein post-translational modifications (PTMs) are crucial for MASLD. However, the functional significance of lysine crotonylation (Kcr) remains unclear. We aimed to investigate the mechanisms by Kcr-regulated IDH1 in the tricarboxylic acid (TCA) cycle and MASLD development. Herein, we reported a quantitative proteomics analysis of global crotonylome upon MASLD and Post-bariatric. Specifically, decreases in K58cr, K151cr, K212cr and K345cr of IDH1 upon MASLD were observed. PCAF and SIRT7 dynamically regulated the IDH1 Kcr. Abolishment of IDH1 Kcr impaired TCA cycle by decreasing IDH1 enzymatic activity. Male mice with liver-specific expression of crotonylation-mimic mutants of IDH1 were resistant to HFD-induced obesity, insulin resistance, glucose intolerance and MASLD. Our findings unravel the mechanisms of IDH1 Kcr and indicate that targeting PCAF/SIRT7-IDH1 Kcr and metabolites may be a promising strategy for MASLD therapy.
    DOI:  https://doi.org/10.1038/s41467-025-62731-9
  21. Sci Adv. 2025 Aug 29. 11(35): eadw9952
    Mitochondrial ROS drive foam cell formation via STAT5 signaling in atherosclerosis.
    Laura Boccuni, Frieda Marka, Manuel Salzmann, Alessia Schirripa, Elisabeth Ableitner, Magdalena Siller, Mira Brekalo, Patrick Haider, Stefan Stojkovic, Christoph Neumayer, Tiit Örd, Karoline Kollmann, Alice Assinger, Thomas Decker, Thomas Köcher, Michael B Fischer, Marion Mußbacher, Andreas Bergthaler, Christian Hengstenberg, Bruno K Podesser, Minna U Kaikkonen, Johann Wojta, Philipp J Hohensinner.
      Macrophage-to-foam cell transition is an integral part of atherosclerotic plaque progression. Particularly, oxidized low-density lipoprotein (oxLDL) is a driving factor in foam cell formation, altering macrophage function and metabolism. The aim of our research was to understand the impact of oxLDL-induced mitochondrial reactive oxygen species on macrophage-to-foam cell differentiation. We demonstrate that macrophage oxLDL-derived superoxide modulates mitochondrial metabolic reprogramming, facilitating foam cell formation. Mechanistically, mitochondrial superoxide drives signal transducers and activators of transcription 5 (STAT5) activation, leading to reduced tricarboxylic acid cycle activity. In parallel, mitochondrial superoxide enhances chromatin accessibility at STAT5 target genes, establishing a distinct STAT5 signaling signature in foam cells ex vivo and in human and mouse plaques in vivo. Inhibition of STAT5 during atherosclerosis progression prevents the differentiation of macrophages to mature Trem2hiGpnmbhi foam cells. Collectively, our data describe an oxLDL-induced, mitochondrial superoxide-dependent STAT5 activation that leads to a self-amplifying feedback loop of reciprocal mitochondrial superoxide production and STAT5 activation, ultimately driving macrophage-to-foam cell transition.
    DOI:  https://doi.org/10.1126/sciadv.adw9952
  22. Nat Med. 2025 Aug 22.
    Ultra-processed diets promote excess calorie consumption.
    Marion Nestle.
      
    DOI:  https://doi.org/10.1038/s41591-025-03910-5
  23. Nat Commun. 2025 Aug 23. 16(1): 7882
    NSUN2 facilitates DICER cleavage of DNA damage-associated R-loops to promote repair.
    Adele Alagia, Kamal Ajit, Arianna Di Fazio, Qilin Long, Monika Gullerova.
      DNA integrity is constantly challenged by both endogenous and exogenous damaging agents, resulting in various forms of damage. Failure to repair DNA accurately leads to genomic instability, a hallmark of cancer. Distinct pathways exist to repair different types of DNA damage. Double-strand breaks (DSBs) represent a particularly severe form of damage, due to the physical separation of DNA strands. The repair of DSBs requires the activity of RNA Polymerase II (RNAPII) and the generation of Damage-responsive transcripts (DARTs). Here we show that the RNA m5C-methyltransferase NSUN2 localises to DSBs in a transcription-dependent manner, where it binds to and methylates DARTs. The depletion of NSUN2 results in an accumulation of nascent primary DARTs around DSBs. Furthermore, we detect an RNA-dependent interaction between NSUN2 and DICER, which is stimulated by DNA damage. NSUN2 activity promotes DICER cleavage of DARTs-associated R-loops, which is required for efficient DNA repair. We report a role of the RNA m5C -methyltransferase NSUN2 within the RNA-dependent DNA damage response, highlighting its function as a DICER chaperone for the clearance of non-canonical substrates such as DARTs, thereby contributing to genomic integrity.
    DOI:  https://doi.org/10.1038/s41467-025-63220-9
  24. Nat Commun. 2025 Aug 27. 16(1): 7204
    Gene expression QTL mapping in stimulated iPSC-derived macrophages provides insights into common complex diseases.
    Nikolaos I Panousis, Omar El Garwany, Andrew Knights, Jesse Cheruiyot Rop, Natsuhiko Kumasaka, Maria Imaz, Lorena Boquete Vilarino, Anthi Tsingene, Alex Tokolyi, Alice Barnett, Celine Gomez, Carl A Anderson, Daniel J Gaffney.
      Many disease-associated variants are thought to be regulatory but are not present in existing catalogues of expression quantitative trait loci (eQTL). We hypothesise that these variants may regulate expression in specific biological contexts, such as stimulated immune cells. Here, we used human iPSC-derived macrophages to map eQTLs across 24 cellular conditions. We found that 76% of eQTLs detected in at least one stimulated condition were also found in naive cells. The percentage of response eQTLs (reQTLs) varied widely across conditions (3.7% - 28.4%), with reQTLs specific to a single condition being rare (1.11%). Despite their relative rarity, reQTLs were overrepresented among disease-colocalizing eQTLs. We nominated an additional 21.7% of disease effector genes at GWAS loci via colocalization of reQTLs, with 38.6% of these not found in the Genotype-Tissue Expression (GTEx) catalogue. Our study highlights the diversity of genetic effects on expression and demonstrates how condition-specific regulatory variation can enhance our understanding of common disease risk alleles.
    DOI:  https://doi.org/10.1038/s41467-025-61670-9
  25. Nat Commun. 2025 Aug 23. 16(1): 7872
    Multi-omic identification of perineurial hyperplasia and lipid-associated nerve macrophages in human polyneuropathies.
    Michael Heming, Anna-Lena Börsch, Jolien Wolbert, Christian Thomas, Anne K Mausberg, Fabian Szepanowski, Bianca Eggert, I-Na Lu, Julia Tietz, Finja Dienhart, Maja Meschnark, Jan-Kolja Strecker, Michael Glatza, Carolina Thomas, Noemi Gmahl, Christine Dambietz, Michael Müther, Anne-Kathrin Uerschels, Kathy Keyvani, Jens Minnerup, Kathrin Doppler, Nurcan Üçeyler, Julieta Aprea, Andreas Dahl, Ruth Stassart, Robert Fledrich, Heinz Wiendl, Claudia Sommer, Mark Stettner, Gerd Meyer Zu Hörste.
      Diseases affecting multiple peripheral nerves, termed polyneuropathies (PNPs), are common, mechanistically heterogeneous, and their causes are challenging to identify. Here, we integrated single-nucleus transcriptomics of peripheral nerves from 33 human PNP patients and four controls (365,708 nuclei) with subcellular spatial transcriptomics. We identified nerve cell type markers and uncovered unexpected heterogeneity of perineurial cells. PNPs shared a loss of myelinating and an increase in repair Schwann cells and endoneurial lipid-phagocytizing macrophages. Transcriptional changes affected multiple cells outside of the endoneurium across PNPs, suggesting PNPs as 'pan-nerve diseases'. Spatially, PNPs-particularly those mediated by autoimmunity-exhibited focal perineurial hyperplasia and increased expression of CXCL14, identified as perineurial cell marker. Multi-omic characterization of human nerve biopsies thus identified novel mechanisms in PNPs with diagnostic potential.
    DOI:  https://doi.org/10.1038/s41467-025-62964-8
  26. Nat Cell Biol. 2025 Aug 27.
    A chaperone-proteasome-based fragmentation machinery is essential for aggrephagy.
    Mario Mauthe, Nicole van de Beek, Muriel Mari, Giel Korsten, Parisa Nobari, Kennith B Castelino, Eduardo P de Mattos, Ibtisam Ouhida, Jesse L Dijkstra, Sabine Schipper-Krom, Laura R de la Ballina, Monja R Mueller, Anne Simonsen, Mark S Hipp, Lukas C Kapitein, Harm H Kampinga, Fulvio Reggiori.
      Perturbations in protein quality control lead to the accumulation of misfolded proteins and protein aggregates, which can compromise health and lifespan. One key mechanism eliminating protein aggregates is aggrephagy, a selective type of autophagy. Here we reveal that fragmentation is required before autophagic clearance of various types of amorphous aggregates. This fragmentation requires both the 19S proteasomal regulatory particle and the DNAJB6-HSP70-HSP110 chaperone module. These two players are also essential for aggregate compaction that leads to the clustering of the selective autophagy receptors, which initiates the autophagic removal of the aggregates. We also found that the same players delay the formation of disease-associated huntingtin inclusions. This study assigns a novel function to the 19S regulatory particle and the DNAJB6-HSP70-HSP110 module, and uncovers that aggrephagy entails a piecemeal process, with relevance for proteinopathies.
    DOI:  https://doi.org/10.1038/s41556-025-01747-1
  27. Proc Natl Acad Sci U S A. 2025 Sep 02. 122(35): e2518203122
    Seeding of visceral adipose tissue with perinatally generated regulatory T cells shapes the metabolic tenor in mice.
    Miguel Marin-Rodero, Teshika Jayewickreme, Christophe Benoist, Diane Mathis.
      The Foxp3+CD4+ regulatory T cells (Tregs) generated around birth are phenotypically and functionally distinct from those engendered during adulthood. That perinatally produced Tregs persist for a protracted period in peripheral lymphoid organs has been well documented, as has their superior ability to protect the organism from many autoimmune diseases. However, their contribution to pools of nonlymphoid-tissue Tregs and their homeostatic functions therein have been little studied. We show that perinatal Tregs preferentially derive from a CD25+Foxp3- thymocyte progenitor; that they seed and persist to varying degrees in every nonlymphoid tissue examined; and that transient depletion of perinatally generated Tregs in adults, but not in neonates, is followed by poor reconstitution of Treg numbers and phenotypes in epididymal visceral-adipose tissue (eVAT) and the skin but not in several lymphoid and other nonlymphoid tissues. Potential clinical implications of such a deficiency are highlighted by findings on mice subjected to weight cycling: Imposing a low-fat-high-fat-low-fat diet regimen in adult, but not juvenile, mice results in an impoverished eVAT, but not spleen, Treg compartment, accompanied by normal weight gain and glucose tolerance but profound insulin resistance. These findings point to a layered immune system, the different layers exerting specialized, nonredundant functions.
    Keywords:  obesity; perinatal; regulatory T cells; type-2 diabetes; weight cycling
    DOI:  https://doi.org/10.1073/pnas.2518203122
  28. Nat Cardiovasc Res. 2025 Aug 26.
    IL6 genetic perturbation mimicking IL-6 inhibition is associated with lower cardiometabolic risk.
    Lanyue Zhang, Murad Omarov, Lingling Xu, Emil deGoma, Pradeep Natarajan, Marios K Georgakis.
      Human genetics supports a causal involvement of IL-6 signaling in atherosclerotic cardiovascular disease, prompting the clinical development of anti-IL-6 therapies. Genetic evidence has historically focused on IL6R missense variants, but emerging cardiovascular treatments target IL-6, not its receptor, questioning the translatability of genetic findings. Here we develop a genetic instrument for IL-6 signaling downregulation comprising IL6 locus variants that mimic the effects of the anti-IL-6 antibody ziltivekimab and use it to predict the effects of IL-6 inhibition on cardiometabolic and safety endpoints. Similar to IL6R, we found that genetically downregulated IL-6 signaling via IL6 perturbation is associated with lower lifetime risks of coronary artery disease, peripheral artery disease and ischemic atherosclerotic stroke in individuals of European and East Asian ancestry. Unlike IL6R missense variants linked to bacterial infections, the IL6 instrument was associated with lower risk of pneumonia hospitalization. Our data suggest that IL-6 inhibition can reduce cardiovascular risk without major unexpected safety concerns.
    DOI:  https://doi.org/10.1038/s44161-025-00700-7
  29. Nat Med. 2025 Aug 25.
    Interplay of genetic predisposition, plasma metabolome and Mediterranean diet in dementia risk and cognitive function.
    Yuxi Liu, Xiao Gu, Yanping Li, Fenglei Wang, Chirag M Vyas, Cheng Peng, Danyue Dong, Yuhan Li, Yu Zhang, Yin Zhang, Oana A Zeleznik, Jae H Kang, Molin Wang, Frank B Hu, Walter C Willett, Olivia I Okereke, A Heather Eliassen, Peter Kraft, Meir J Stampfer, Dong D Wang.
      Alzheimer's disease (AD) and AD-related dementias (AD/ADRD) have a substantial genetic basis, with APOE4 homozygotes increasingly recognized as a distinct genetic subtype. To identify genotype-specific metabolic pathways and modifiable risk factors, we integrated genetic, plasma metabolomic and dietary data from 4,215 women and 1,490 men in prospective cohorts. Here we show that the associations of 57 metabolites with dementia risk varied by APOE4 genotype or other AD/ADRD risk variants. For example, cholesteryl esters and sphingomyelins were most strongly associated with increased dementia risk in APOE4 homozygotes, whereas inverse associations with glycerides were specific to this genotype. Dimethylguanidino-valeric acid was more strongly associated with dementia risk among carriers of the rs2154481-C allele (APP). Adherence to the Mediterranean diet more effectively modulated dementia-related metabolites in APOE4 homozygotes, suggesting targeted prevention strategies. Incorporating metabolomic data modestly improved dementia risk prediction, particularly during early follow-up. Mendelian randomization analysis identified 19 putative causal relationships between metabolites and cognitive outcomes, including protective effects of 4-guanidinobutanoate, carotenoids and N6-carbamoylthreonyladenosine. These findings reveal genotype-dependent metabolic profiles of cognitive health and support precision nutrition approaches for ADRD prevention.
    DOI:  https://doi.org/10.1038/s41591-025-03891-5
  30. Nat Metab. 2025 Aug 22.
    Investigating metabolic changes in single embryos during early development in Drosophila.
      
    DOI:  https://doi.org/10.1038/s42255-025-01375-x
  31. Nature. 2025 Aug 20.
    Quantitative imaging of lipid transport in mammalian cells.
    Juan M Iglesias-Artola, Kristin Böhlig, Kai Schuhmann, Katelyn C Cook, H Mathilda Lennartz, Milena Schuhmacher, Pavel Barahtjan, Cristina Jiménez López, Radek Šachl, Vannuruswamy Garikapati, Karina Pombo-Garcia, Annett Lohmann, Petra Riegerová, Martin Hof, Björn Drobot, Andrej Shevchenko, Alf Honigmann, André Nadler.
      Eukaryotic cells produce over 1,000 different lipid species that tune organelle membrane properties, control signalling and store energy1,2. How lipid species are selectively sorted between organelles to maintain specific membrane identities is largely unclear, owing to the difficulty of imaging lipid transport in cells3. Here we measured the retrograde transport and metabolism of individual lipid species in mammalian cells using time-resolved fluorescence imaging of bifunctional lipid probes in combination with ultra-high-resolution mass spectrometry and mathematical modelling. Quantification of lipid flux between organelles revealed that directional, non-vesicular lipid transport is responsible for fast, species-selective lipid sorting, in contrast to the slow, unspecific vesicular membrane trafficking. Using genetic perturbations, we found that coupling between energy-dependent lipid flipping and non-vesicular transport is a mechanism for directional lipid transport. Comparison of metabolic conversion and transport rates showed that non-vesicular transport dominates the organelle distribution of lipids, while species-specific phospholipid metabolism controls neutral lipid accumulation. Our results provide the first quantitative map of retrograde lipid flux in cells4. We anticipate that our pipeline for mapping of lipid flux through physical and chemical space in cells will boost our understanding of lipids in cell biology and disease.
    DOI:  https://doi.org/10.1038/s41586-025-09432-x
  32. Hepatology. 2025 Sep 01. 82(3): 655-668
    CX3CR1+ macrophages interact with HSCs to promote HCC through CD8+ T-cell suppression.
    Jong-Min Jeong, Sung Eun Choi, Young-Ri Shim, Hee-Hoon Kim, Young-Sun Lee, Keungmo Yang, Kyurae Kim, Min Jeong Kim, Katherine Po Sin Chung, Seok-Hwan Kim, Jin-Seok Byun, Hyuk Soo Eun, Won-Il Jeong.
       BACKGROUND AND AIMS: HSCs contribute to HCC progression by regulating multiple factors. However, the entire immunoregulatory functions of HSCs are still obscure. Here, we aim to investigate whether HSCs impose CX3CR1+ macrophages to protumorigenic properties in the peritumoral area.
    APPROACH AND RESULTS: In single-cell RNA-sequencing analysis of patients with HCC, a subpopulation of macrophages specifically expressed Arg1 and Cx3cr1 in the peritumoral area and were highly enriched with retinol metabolism-related genes. Flow cytometry analysis showed significantly increased frequencies of CD14+CD11b+HLA-DR- macrophages with CX3CR1 in the HCC adjacent region where α-smooth muscle actin-expressing activated hepatic stellate cells (aHSCs) showed colocalized expression of CX3CL1. Accordingly, in tumor-bearing mice, Cx3cl1 mRNA expression was notably increased in aHSCs within the adjacent HCC, where infiltration of CX3CR1+Ly6C+ macrophages was mostly observed with decreased CD8+ T cells. In adoptive transfer and in vitro coculture of myeloid cells, we demonstrated that CX3CR1+Ly6C+ macrophages migrated and highly expressed arginase-1 by interacting with retinoid-enriched aHSCs in the adjacent HCC. Direct treatment of retinoids or coculturing with retinol-storing mouse aHSCs or human LX-2 cells significantly increased arginase-1 expression in CX3CR1+Ly6C+ macrophages and human blood CD14+ cells, leading to the suppression of CD8+ T-cell proliferation. Moreover, genetic deficiency of CX3CR1 in myeloid cells or pharmacological inhibition of retinol metabolism remarkably attenuated HCC development.
    CONCLUSIONS: We showed that CX3CR1+Ly6C+ macrophages migrate and interact with aHSCs in the peritumoral region where retinoids induce arginase-1 expression in CX3CR1+Ly6C+ macrophages, subsequently depriving CD8+ T cells of arginine and promoting HCC.
    DOI:  https://doi.org/10.1097/HEP.0000000000001021
  33. Nat Commun. 2025 Aug 26. 16(1): 7951
    ALS/FTD-linked TBK1 deficiency in microglia induces an aged-like microglial signature and drives social recognition deficits in mice.
    Isadora Lenoel, Matthieu Ribon, Félicie Lorenc, Aurélien Diebold, Clementine E Philibert, David Robaldo, Manel Badsi, Julianne Perronnet, Julie Lameth, Felix Berriat, Hidemi Misawa, Marie Coutelier, Raphaelle Cassel, Nadège Sarrazin, Coline Jost-Mousseau, Delphine Bohl, Stéphanie Millecamps, Michel Mallat, David Brenner, Jochen H Weishaupt, Séverine Boillée, Christian S Lobsiger.
      TANK-Binding Kinase 1 (TBK1) is involved in autophagy and immune signaling. Dominant loss-of-function mutations in TBK1 have been linked to Amyotrophic Lateral Sclerosis (ALS), Fronto-temporal dementia (FTD), and ALS/FTD. However, pathogenic mechanisms remain unclear, particularly the cell-type specific disease contributions of TBK1 mutations. Here, we show that deleting Tbk1 from mouse motor neurons does not induce transcriptional stress, despite lifelong signs of autophagy deregulations. Conversely, Tbk1 deletion in microglia alters their homeostasis and reactive responses. In both spinal cord and brain, Tbk1 deletion leads to a pro-inflammatory, primed microglial signature with features of ageing and neurodegeneration. While it does not induce or modify ALS-like motor neuron damage, microglial Tbk1 deletion is sufficient to cause early FTD-like social recognition deficits. This phenotype is linked to focal microglial activation and T cell infiltration in the substantia nigra pars reticulata and pallidum. Our results reveal that part of TBK1-linked FTD disease originates from microglial dysfunction.
    DOI:  https://doi.org/10.1038/s41467-025-63211-w
  34. Nat Cardiovasc Res. 2025 Aug 21.
    Region-specific gene expression and sex inform about disease susceptibility in the aorta.
    Milagros C Romay, Feiyang Ma, Ana Mompeón, Michele Silvestro, Gloria E Hernandez, Jocelynda Salvador, Andrew L Wang, Marie Vandestienne, Nathalie Bardin, Marcel Blot-Chabaud, Aurelie S Leroyer, Hafid Ait-Oufella, Bhama Ramkhelawon, M Luisa Iruela-Arispe.
      Pathology in large vessels frequently develops at specific locations, implying that local stressors and spatially restricted gene expression are likely contributors to disease susceptibility. Here we perform single-cell transcriptomics in the carotids, the aortic arch and the thoracic and abdominal aorta to identify site- and sex-specific differences that could inform about vulnerability. Our findings revealed (1) regionally defined transcriptional profiles, (2) signatures associated with embryonic origins and (3) differential contributions of sex-specific effectors. Furthermore, cross-referencing regional-specific signatures with available genome-wide association study and expression quantitative trait loci databases identified 339 disease candidates associated with aorta distensibility, stiffness index and blood pressure. CPNE8 and SORBS2 were further evaluated and highlighted as strong causal candidates. Sex differences were predominantly observed in the thoracic and abdominal aorta. MCAM (CD146), a transcript with sex-skewed expression and lower in male mice and men, had significantly reduced expression in human aortic aneurysms. The findings reveal underlying diversity within vascular smooth muscle cell populations relevant to understanding site-specific and sex-specific variation of vascular pathologies.
    DOI:  https://doi.org/10.1038/s44161-025-00692-4
  35. Nature. 2025 Aug 27.
    Viral spread: how rumours surged in revolutionary France.
    Benjamin Thompson, Nick Petrić Howe.
      
    Keywords:  Cosmology; Epidemiology; Physics
    DOI:  https://doi.org/10.1038/d41586-025-02749-7
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