bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2026–08–16
twenty papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. The cost of persistence: MEK and metabolic demand.
  2. Human brain stimulation engages different gene programs in different cell types.
  3. GDF15 suppresses liver inflammation independently of weight loss through neuroendocrine glucocorticoid signaling.
  4. Youth-associated protein TIMP2 regulates microglial state and function in healthy and aged mice.
  5. Type 2 diabetes prevention across the life course.
  6. TIF1γ holds the line against regulatory T cell plasticity.
  7. A single-cell multi-omic atlas of the human pancreas reveals potential for cellular plasticity across development, health, and disease.
  8. LRP5-dependent transport of polyunsaturated fatty acids serves as an immune checkpoint for natural killer cells.
  9. Weight-loss-independent actions of GLP-1 medicines.
  10. Advanced imaging of membrane contact sites.
  11. Decoding neural signals to build metabolic therapies.
  12. Regulation of inflammation by oxidized lipids.
  13. The Hormone Cell Atlas decodes the human endocrine system, one cell at a time.
  14. Genetic Predisposition and Pharmacological Effects Shape the Divergent Effects of Type 2 Diabetes on Atherosclerosis.
  15. S100A11 regulates hepatic cholesterol metabolism and promotes steatohepatitis via non-canonical SREBP2 signaling.
  16. Metabolic Reprogramming of Brain Microglia: Implications for Aging and Aging-Associated Neurodegenerative Diseases.
  17. Redrawing the lines for the management of obesity in Asia.
  18. Metabolic stress-activated endothelial STING rewires the sinusoidal immune niche in MASLD.
  19. Zfp217 Regulates Hepatic de Novo Lipogenesis via METTL3-Mediated N6-Methyladenosine Modification of SREBF1.
  20. Brain perivascular macrophages regulate endothelial cell function via a cMAF-dependent transcriptional program in mouse and human.
  1. Immunity. 2026 Aug 11. pii: S1074-7613(26)00311-0. [Epub ahead of print]59(8): 2058-2060
    The cost of persistence: MEK and metabolic demand.
    Ewelina Sobierajska, Christopher B Medina.
      The metabolic mechanisms linking chronic TCR stimulation to T cell exhaustion remain incompletely understood. Mitra and colleagues show that sustained MEK signaling drives the bioenergetic demands of chronic activation to promote terminal exhaustion, whereas MEK inhibition maintains progenitor-like T cells.
    DOI:  https://doi.org/10.1016/j.immuni.2026.07.012
  2. Nature. 2026 Aug 12.
    Human brain stimulation engages different gene programs in different cell types.
      
    Keywords:  Brain; Genetics; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-026-02473-w
  3. Cell Metab. 2026 Aug 10. pii: S1550-4131(26)00281-0. [Epub ahead of print]
    GDF15 suppresses liver inflammation independently of weight loss through neuroendocrine glucocorticoid signaling.
    Dongdong Wang, Maria Joy Therese Jabile, Fiorella Di Pastena, Logan K Townsend, Elham Ahmadi, Annabelle Hoegl, Alice Payne, Declan C T Lavoie, Battsetseg Batchuluun, Jaya Gautam, Marisa R Morrow, James S V Lally, Rune E Kuhre, Sebastian B Jørgensen, Gregory R Steinberg.
      Growth differentiation factor 15 (GDF15) is strongly associated with metabolic dysfunction-associated steatohepatitis (MASH), yet whether it promotes or protects against liver injury remains unclear. Using thermoneutral mouse models that closely resemble human MASH, genetic deletion of GDF15 or its receptor GFRAL selectively worsened hepatic inflammation and fibrosis without altering steatosis or insulin resistance. Conversely, recombinant GDF15 reduced liver inflammation and fibrosis more effectively than matched caloric restriction despite identical reductions in food intake, body weight, and steatosis, demonstrating weight-loss-independent hepatoprotection. These effects required GFRAL but were independent of β-adrenergic signaling. Instead, GDF15 activated the hypothalamic-pituitary-adrenal (HPA) axis, increasing circulating corticosterone and hepatic glucocorticoid receptor signaling. Spatial transcriptomics and RNA sequencing demonstrated that GDF15 remodeled the hepatic immune-fibrotic niche by suppressing inflammatory macrophages, plasma B cells, and activated stellate cells while promoting pro-resolving immune programs. Together, these findings identify a GDF15-GFRAL-HPA axis that restrains liver inflammation independently of weight loss.
    Keywords:  GFRAL; HPA; Kupffer cells; MASLD; RNA sequence; caloric restriction; glucocorticoid receptor; hypothalamic-pituitary-adrenal axis
    DOI:  https://doi.org/10.1016/j.cmet.2026.07.008
  4. Nat Commun. 2026 Aug 12. pii: 8173. [Epub ahead of print]17(1):
    Youth-associated protein TIMP2 regulates microglial state and function in healthy and aged mice.
    Brittany M Hemmer, Sarah M Philippi, Ana Catarina Ferreira, Samuele F Petridis, Annie Phan, Joseph M Castellano.
      There is little understanding of how aging serves as the strongest risk factor for several neurodegenerative diseases. Microglia undergo age-related maladaptive changes, including increased inflammation, impaired debris clearance, and cellular senescence, yet specific mediators that regulate these processes remain unclear. The aged brain is rejuvenated by youth-associated plasma factors, including tissue inhibitor of metalloproteinases 2 (TIMP2), which we have shown acts on the extracellular matrix (ECM) to regulate synaptic plasticity. Given emerging roles for microglia in these processes, we examined the impact of TIMP2 on microglial function. We show that TIMP2 deletion in mice exacerbates microglial phenotypes associated with aging, including transcriptomic changes in cell activation, changes in lysosomal-associated markers and phagocytosis, and elevated levels of stress and inflammatory proteins in the brain extracellular space measured by in vivo microdialysis. Deleting specific cellular pools of TIMP2 in vivo increases microglial CD68 and alters myelin phagocytosis. Treating aged mice with TIMP2 reverses several phenotypes observed in our deletion models, resulting in decreased microglial activation, reduced proportions of proinflammatory microglia, and enhanced phagocytosis of physiological substrates. Our results identify TIMP2 as a modulator of age-associated microglia dysfunction. Harnessing its activity may mitigate detrimental effects of age-associated insults on microglia function.
    DOI:  https://doi.org/10.1038/s41467-026-74906-z
  5. Nat Med. 2026 Aug;32(8): 2757-2773
    Type 2 diabetes prevention across the life course.
    Yiying Wang, Jennifer L Sargent, Chantal Mathieu, Elsa Vazquez-Arreola, Leigh Perreault, Ruth J F Loos, Lee-Ling Lim, Leontine Sandforth, Robert L Hanson, Stephanie Kullmann, Julia Sbierski-Kind, Sara Y Brucker, Martin Hrabé de Angelis, Fabian Theiss, Andrea Icks, Damon Mohebbi, Norbert Stefan, Viswanathan Mohan, Tiange Wang, Hubert Preissl, Michael Bergman, Jaakko Tuomilehto, Marie-France Hivert, Paul W Franks, Andreas L Birkenfeld.
      Type 2 diabetes (T2D) prevention efforts have largely focused on intervening when dysglycemia is already established. We propose that T2D prevention be reframed around prediabetes remission, with preservation and restoration of normoglycemia as the optimal clinical goal. The transition from normoglycemia through increasing dysglycemia to T2D is progressive and cumulatively shaped by biological, behavioral and environmental exposures across the life course. Prediabetes (intermediate hyperglycemia) remission is an achievable, pragmatic and measurable prevention target. Here we provide a life-course risk architecture for T2D integrating developmental, transitional and contextual determinants, defining critical windows of amplified metabolic vulnerability and potential restoration of normoglycemia. Precision prevention should target mechanistic heterogeneity, with aligned interventions that remain scalable, affordable and adaptable across socioeconomic settings. Our framework identifies ten priorities in T2D prevention, moving beyond traditional approaches toward context-specific, actionable interventions capable of altering the natural history of disease early in the life course and restoring metabolic health.
    DOI:  https://doi.org/10.1038/s41591-026-04550-z
  6. Nat Immunol. 2026 Aug 14.
    TIF1γ holds the line against regulatory T cell plasticity.
    Fotini Gounari, Khashayarsha Khazaie.
      
    DOI:  https://doi.org/10.1038/s41590-026-02620-5
  7. Cell Metab. 2026 Aug 12. pii: S1550-4131(26)00296-2. [Epub ahead of print]
    A single-cell multi-omic atlas of the human pancreas reveals potential for cellular plasticity across development, health, and disease.
    Elisabetta Mereu, Diego Balboa, Johannes Liebig, Aitor Gonzalez-Herrero, Anna Martinez Casals, Mariya Mardamshina, Fanny Mollandin, Felix Schicktanz, Alexander Sudy, Luca Tosti, Maarten van Agen, Valerie Vandenbempt, Dana Avrahami, Frederic Ballllosera Navarro, Edgar Bernardo, Frida Björklund, Robert Lorenz Chua, Marten Engelse, Javier García-Hurtado, Nathalie Groen, Maaike Hanegraaf, Pablo Iañez, Katharina Jechow, Björn Konukiewitz, Christian Lawerenz, Nadja Lewandowski-Hoppe, Domenica Marchese, Mauro J Muraro, Silvia Pellegrini, Valeria Sordi, Ulrike Taron, Foo Wei Ten, Timo Trefzer, Sven Twardziok, Johannes Wirth, Françoise Carlotti, Eelco de Koning, Jorge Ferrer, Benjamin Glaser, Holger Heyn, Emma Lundberg, Lorenzo Piemonti, Katja Steiger, Alexander van Oudenaarden, Wilko Weichert, Christian Conrad, Roland Eils.
      The pancreas plays a central role in major human diseases, yet our understanding of its cellular diversity and plasticity remains incomplete. Here, we present a single-cell multiomics atlas of the human pancreas, profiling over four million cells and nuclei from 57 donors across fetal development, adult homeostasis, and type 2 diabetes (T2D). Integrating single-cell RNA sequencing (scRNA-seq)/single-nucleus RNA sequencing (snRNA-seq), snATAC-seq, VASA-seq, spatial transcriptomics (Xenium), and multiplexed proteomics (CODEX), we resolve gene expression, chromatin accessibility, and spatial organization at high resolution. We identify transcriptionally plastic centroacinar-like cells (pCACs) in adults with fetal-like features, delineate endocrine and exocrine lineage trajectories during development, and define HNF1A-defined beta cell epigenetic states. In T2D, we observe shifts in beta cell subtypes and altered regulatory programs. Glucose perturbation of healthy islets reveals cell-type-specific adaptation and stress responses. This atlas provides a foundational framework to understand pancreas biology and the role of cellular plasticity in regeneration and disease.
    Keywords:  HNF1A regulatory states; centroacinar-like cells; developmental trajectories; human pancreas; ionocyte-like ductal cells; pancreatic plasticity; single-cell multiomics; spatial omics; type 2 diabetes; β cell heterogeneity
    DOI:  https://doi.org/10.1016/j.cmet.2026.07.023
  8. Sci Signal. 2026 Aug 11. 19(950): eady2865
    LRP5-dependent transport of polyunsaturated fatty acids serves as an immune checkpoint for natural killer cells.
    Yi Luan, Chuan Yang, Hongyue Zhou, Zhuo Chen, Ao Li, Peng Liu, Dianqing Wu, Wenwen Tang.
      Polyunsaturated fatty acids (PUFAs) play a crucial role in tumor development by influencing not only tumor cells but also immune cells within the tumor microenvironment. Here, we explored the mechanisms by which PUFAs are transported and function within immune cells to regulate tumor growth. We found that PUFA transport through LDL receptor-related protein 5 (LRP5) into natural killer (NK) cells played an essential role in modulating the cells' antitumor function. LRP5 deficiency or expression of LRP5 lacking the LDLa domain enhanced the cytotoxicity and antitumor activity of NK cells both in vivo and in culture. However, wild-type NK cells cultured in the absence of PUFAs and NK cells from mice fed a PUFA-free diet also exhibited enhanced cytotoxicity, eliminating the functional difference between wild-type and NK cells expressing LDLa domain-deficient LRP5. Mechanistically, LRP5-mediated PUFA transport suppressed mTORC1 signaling and glycolysis in NK cells, a metabolic pathway essential for NK cell cytotoxicity. Thus, our study identified LRP5 as an immune checkpoint that restrains NK cell activity through PUFA transport-dependent suppression of mTORC1 signaling.
    DOI:  https://doi.org/10.1126/scisignal.ady2865
  9. Cell Metab. 2026 Aug 04. pii: S1550-4131(26)00279-2. [Epub ahead of print]38(8): 1535-1539
    Weight-loss-independent actions of GLP-1 medicines.
    Maria J Gonzalez-Rellan, Daniel J Drucker.
      The unprecedented broad efficacy of GLP-1 medicines reflects mechanisms beyond weight loss. GLP-1R agonism recruits neural and immune circuits, inter-organ communication, and engages local GLP-1Rs to improve cardiovascular, renal, hepatic, musculoskeletal, and organismal health. Defining dose-response relationships for weight-loss-independent mechanisms will facilitate optimization of the therapeutic potential of GLP-1 medicines.
    DOI:  https://doi.org/10.1016/j.cmet.2026.07.006
  10. Nat Cell Biol. 2026 Aug;28(8): 1612-1625
    Advanced imaging of membrane contact sites.
    Riccardo Filadi, Ambra Bertocco, Michela Rossini, Paola Pizzo.
      Organelle membrane contact sites (MCSs) coordinate key cell activities and their alterations are associated with several high-incidence disorders, prompting an increasing interest in their study. However, the investigation of MCSs is challenging, mostly because of their nanometric size and dynamic nature. Here we highlight the methods that are available for analysing MCSs. We focus on advanced imaging techniques and discuss their advantages and limitations, providing practical guidance for researchers approaching this field. We propose to study MCSs through a combination of different methodologies, complementing their visualization with investigation of the associated functions. To this end, we also discuss the need to develop innovative biosensors.
    DOI:  https://doi.org/10.1038/s41556-026-02003-w
  11. Cell Metab. 2026 Aug 04. pii: S1550-4131(26)00236-6. [Epub ahead of print]38(8): 1513-1517
    Decoding neural signals to build metabolic therapies.
    Tune H Pers, Amber L Alhadeff, Martin G Myers, Alice E Adriaenssens, Henning Fenselau, Sarah A Stanley, Virginie Mansuy-Aubert, Ana I Domingos, Alejandro Caicedo, Beste Mutlu.
      Ongoing research points to neural circuits as the major targets for the incretin-mimetic drugs that are transforming obesity treatment. In this Voices piece, we asked researchers to discuss their work on how central and peripheral pathways influence energy balance and metabolism, and what next steps are needed to therapeutically target these pathways.
    DOI:  https://doi.org/10.1016/j.cmet.2026.06.010
  12. Sci Immunol. 2026 Aug 14. 11(122): eadv9397
    Regulation of inflammation by oxidized lipids.
    Marco Di Gioia, Ivan Zanoni.
      Host-derived lipids undergoing enzymatic or nonenzymatic oxidation play critical roles in regulating inflammation. Polyunsaturated fatty acids, cholesterol, and cholesterol intermediates can be enzymatically oxidized and serve as signaling mediators controlling tissue homeostasis and immunity. Spontaneously generated oxidized lipids, including nonenzymatically oxidized phospholipids (oxPLs), result from oxidative stress and accumulate during inflammation, affecting cellular metabolism, immune cell functions, and cell fate. These distinct classes of oxidized lipids not only share overlapping inflammatory roles but also exhibit divergent effects depending on their molecular structures and cellular targets. This Review highlights the double-edged nature of oxPLs: Although their transient production triggers protective responses, their accumulation sustains inflammation, contributing to tissue damage. We also discuss the emerging roles of oxPLs in cell death programs, immune cell activation, and stromal cell functions, which are critical processes favoring tumor growth. Overall, we highlight how oxidized lipids orchestrate immune responses and explore their contribution to infectious diseases and cancer.
    DOI:  https://doi.org/10.1126/sciimmunol.adv9397
  13. Cell Metab. 2026 Aug 04. pii: S1550-4131(26)00245-7. [Epub ahead of print]38(8): 1529-1530
    The Hormone Cell Atlas decodes the human endocrine system, one cell at a time.
    Dominique Langin, André C Carpentier.
      Farooqi, Teichmann, and collaborators developed the Hormone Cell Atlas, a 14-million-cell dataset mapping hormone production and sensitivity across 47 human tissues. Their findings expand knowledge on sites of production and receiver cells, opening new avenues in endocrinology and metabolism.
    DOI:  https://doi.org/10.1016/j.cmet.2026.06.019
  14. Genomics Proteomics Bioinformatics. 2026 Aug 08. pii: qzag079. [Epub ahead of print]
    Genetic Predisposition and Pharmacological Effects Shape the Divergent Effects of Type 2 Diabetes on Atherosclerosis.
    Shufen Zheng, Yonglin Wu, Aijie Li, Zhuoyi Wu, Zhen Liu, Huawei Wang, Xiaoyan Jia, Philip S Tsao, Cuiping Pan.
      Type 2 diabetes mellitus (T2D) increases the risk of atherosclerotic diseases, including coronary artery disease (CAD), but decreases that for abdominal aortic aneurysm (AAA), forming an intriguing diabetes-atherosclerosis paradox. We investigate how genetic underpinnings and drug effects shape these complex relationships. A robust positive correlation between T2D and CAD is found throughout the genome, whereas the weak genetic correlation between T2D and AAA is counter-balanced by two-thirds positive and one-third negative correlations. Through single nucleotide variant colocalization, gene annotation, pathway enrichment, and cell type associations, we discover that these positive correlations entail immune responses, whereas the negative correlation is characterized by beta-cell dysfunction and lipid metabolism. Furthermore, the effects of 98 canonical cardiovascular and metabolic drugs are elucidated by pathway pairing and drug-target Mendelian Randomization, revealing that the widely prescribed metformin and glitazones are also protective against atherosclerosis, whereas statins raise the T2D risk. Through screening the plasma proteome against 660 anti-inflammatory drugs, we identify 14 targets and 8 drugs for anti-inflammatory treatments of T2D and atherosclerosis. Our study discovers that both disease-disease and drug-disease interplay contribute to the complex relationships between diabetes and atherosclerosis. Importantly, immune responses synergize with diabetes and atherosclerotic diseases, suggesting anti-inflammatory therapies as a unified treatment strategy.
    Keywords:  Atherosclerotic disease; Drug effect; Genetic basis; Network pharmacology; Type 2 diabetes
    DOI:  https://doi.org/10.1093/gpbjnl/qzag079
  15. J Clin Invest. 2026 Aug 04. pii: e201406. [Epub ahead of print]
    S100A11 regulates hepatic cholesterol metabolism and promotes steatohepatitis via non-canonical SREBP2 signaling.
    Mingfeng Zhan, Xiumei Xu, Huiyin Wu, Qijing Fan, Hongsheng Lu, Chengbin Li, Linqiang Zhang, Tingting Zhu, Yunqian Shen, Jing Liu, Yaomei He, Yingjie Wu, Jingjing Zhang, Xiaoju Zou, Bin Liang.
      Dietary cholesterol and de novo cholesterol synthesis in the liver use reciprocal coordination to maintain cholesterol homeostasis. However, high level of dietary cholesterol still promotes excessive cholesterol accumulation in the liver, leading to metabolic dysfunction-associated steatohepatitis (MASH), yet the mechanisms remain poorly understood. Here we show that hepatic S100A11, a member of the S100 family of calcium-binding proteins, positively responds to the dietary cholesterol level and is involved in hepatic cholesterol metabolism. S100A11 localizes to the endoplasmic reticulum and can bind to cholesterol. In vivo and in vitro, hepatic overexpression of S100A11 led to SREBP2 activation to promote cholesterol synthesis, uptake, and accumulation, consequently exacerbating steatohepatitis. In contrast, inactivation of S100A11 had opposite effects and improved steatohepatitis. Mechanistically, S100A11 triggers the non-canonical entry of SREBP2 into the nucleus through a S100A11-ANXA1-KPNB axis, distinct from the well-known INSIG-SCAP pathway or Caspase2 pathways. Therefore, our work identifies S100A11 as a regulator of liver cholesterol metabolism, providing a promising target to treat MASH and hypercholesterolemia.
    Keywords:  Cholesterol; Hepatitis; Hepatology; Homeostasis; Inflammation
    DOI:  https://doi.org/10.1172/JCI201406
  16. Aging Cell. 2026 Aug;25(8): e70660
    Metabolic Reprogramming of Brain Microglia: Implications for Aging and Aging-Associated Neurodegenerative Diseases.
    Seokjo Kang, Helen S Goodridge.
      Microglia, the resident macrophages of the central nervous system (CNS), are key players in maintaining brain and spinal cord homeostasis and protecting the CNS from damage and disease. During aging, the brain undergoes profound changes-including chronic low-grade inflammation, synaptic dysfunction, and increased vulnerability to neurodegenerative diseases-all of which are closely related to alterations in microglial function. One emerging theme is that microglial metabolism is a crucial determinant of their immune and homeostatic activity. In this mini-review, we explore how metabolic programs shape brain microglial behavior and how these processes change during aging and in neurodegenerative diseases. We first highlight the link between specific metabolic pathways and key microglial functions, including phagocytosis, cytokine production, and the oxidative stress response. We then discuss how microglial metabolism is reprogrammed during healthy aging and in Alzheimer's disease and Parkinson's disease, including sex-specific differences. Finally, we examine regulators that influence microglial metabolic states and discuss how these pathways contribute to disease susceptibility and progression. Collectively, recent findings highlight the central role of metabolic reprogramming in shaping microglial responses during aging and in neurodegenerative diseases. We emphasize the need for integrative studies that consider microglial subsets, sex differences, disease context, and upstream molecular regulators to better understand how microglial metabolism contributes to brain health and pathology. A deeper understanding of these pathways may offer new opportunities for therapeutic strategies aimed at restoring microglial homeostasis and mitigating harmful neuroinflammatory processes.
    Keywords:  Alzheimer's disease; Parkinson's disease; brain aging; metabolism; microglia; neuroinflammation; sex differences
    DOI:  https://doi.org/10.1111/acel.70660
  17. Lancet Diabetes Endocrinol. 2026 Aug 10. pii: S2213-8587(26)00155-5. [Epub ahead of print]
    Redrawing the lines for the management of obesity in Asia.
    Bernard Khoo.
      
    DOI:  https://doi.org/10.1016/S2213-8587(26)00155-5
  18. J Clin Invest. 2026 Aug 06. pii: e207031. [Epub ahead of print]
    Metabolic stress-activated endothelial STING rewires the sinusoidal immune niche in MASLD.
    Zhi-Bin Lin, Peng Zou, Xian-Yi Ma, Jun-Bo Song, Hong Zhang, Wei Du, Dan Wei, Ping Song, Xin Hong, Jingjing Liu, Zhi-Qiang Fang, Hao Xu, Fei He, Juan-Li Duan, Ke-Feng Dou, Lin Wang.
      Liver sinusoidal endothelial cells (LSECs) regulate nutrient flux and immune surveillance within the hepatic niche, yet how they function as metabolic stress sensors that instruct adaptive immune remodeling during metabolic dysfunction-associated steatotic liver disease (MASLD) remains unclear. Here, single-nucleus transcriptomics of human MASLD reveals stage-dependent activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling in LSEC comparable to that in macrophage, with endothelial activation showing greater responsiveness to metabolic stress. Endothelial-specific STING deletion attenuates steatohepatitis and fibrosis in mice. Mechanistically, LSEC-intrinsic STING activation reprograms the angiocrine landscape through NF-κB-mediated transcriptional repression of the endothelial-derived factor BMP4. Loss of BMP4 disrupts the tolerance-supporting sinusoidal immunometabolic niche, skewing CD4⁺ T cell differentiation toward pathogenic Th17 states while destabilizing Treg, collectively exacerbating hepatic metabolic failure. In human MASLD, endothelial STING activity inversely correlates with BMP4 expression at single-cell resolution. Targeted delivery of a STING inhibitor to LSECs using peptide-functionalized nanoparticles restores hepatic metabolic-immune balance at one-tenth the systemic dose. Together, these findings establish endothelial STING as a metabolically responsive vascular immune checkpoint that links chronic metabolic stress to adaptive immune remodeling and fibrotic progression.
    Keywords:  Fibrosis; Hepatology; Innate immunity; Metabolism; Molecular biology
    DOI:  https://doi.org/10.1172/JCI207031
  19. FASEB J. 2026 Aug 15. 40(15): e72150
    Zfp217 Regulates Hepatic de Novo Lipogenesis via METTL3-Mediated N6-Methyladenosine Modification of SREBF1.
    Shuangshuang Li, Qianhui Zeng, Yadan Liu, Yiqi Li, Nannan Wang, Rong Zheng, Bo Zuo, Yuanfei Zhou, Siwen Jiang.
      Zinc finger protein 217 (Zfp217) mediates adipogenesis via an N6-methyladenosine (m6A)-dependent mechanism; however, its role in hepatic lipid metabolism is unexplored. Nonalcoholic fatty liver disease (NAFLD), characterized by hepatic triglyceride (TG) accumulation resulting from disrupted lipid homeostasis, lacks well-defined epigenetic regulatory mechanisms. Here, we report that global Zfp217 heterozygous knockout alleviates high-fat diet (HFD)-induced hepatic steatosis in mice, as evidenced by reduced liver weight, decreased hepatic and serum TG and total cholesterol (T-CHO) levels, and hepatic lipid deposition. Mechanistically, Zfp217 deficiency suppresses hepatic de novo lipogenesis (DNL) by down-regulating sterol regulatory element-binding transcription factor 1 (SREBF1), a master regulator of lipogenic gene expression. Zfp217 physically interacts with methyltransferase-like 3 (METTL3) to repress its expression, thereby reducing m6A modification of SREBF1 mRNA at a specific coding sequence (CDS) site. Loss of Zfp217 enhances METTL3-dependent m6A modification at a specific site of SREBF1 mRNA, which promotes YTH domain-containing family protein 2 (YTHDF2)-mediated degradation of SREBF1 transcripts. Conversely, our findings identify a novel Zfp217-METTL3-m6A-YTHDF2-SREBF1 regulatory axis that controls hepatic DNL and NAFLD progression, establishing Zfp217 as a potential therapeutic target for NAFLD.
    Keywords:  METTL3; SREBF1; Zfp217; hepatic de novo lipogenesis; hepatic steatosis; m6A methylation
    DOI:  https://doi.org/10.1096/fj.202600780RR
  20. Cell. 2026 Aug 14. pii: S0092-8674(26)00875-5. [Epub ahead of print]
    Brain perivascular macrophages regulate endothelial cell function via a cMAF-dependent transcriptional program in mouse and human.
    Simone Brioschi, Julia A Belk, Steffen E Storck, Yue Wu, Zhuoying Wang, Ziang Feng, Lynn van Olst, Josie L Emery, Raki Sudan, Junjie Wu, Siling Du, Marco Genua, Federica La Terza, Alex J Edwards, Khai M Nguyen, Jessie Sanford, Daniel D Lee, Mattia Bugatti, Arnold J Federico, Yun Chen, Zuoxu Wang, Silvia Penati, Patrick Fernandes Rodrigues, Alina Ulezko Antonova, Hui Qi Loo, Igor Smirnov, Susan Gilfillan, Carmen M Halabi, Jennifer Ponce, Jun Yan, Howard Y Chang, Gwendalyn J Randolph, William Vermi, Marina Cella, Michael Meers, Renato Ostuni, David Gate, Aivi T Nguyen, Carlos Cruchaga, Song Hu, Jonathan Kipnis, Marco Colonna.
      Brain perivascular macrophages maintain brain physiology, yet their transcriptional regulators and functions in health and disease remain unclear. Using single-cell multi-omics and functional experiments, we identify cellular musculoaponeurotic fibrosarcoma oncogene (cMAF) as a key transcription factor for brain perivascular macrophages, and conditional deletion of cMAF disrupts their phenotype in vivo. Functionally, cMAF drives insulin-like growth factor-1 (IGF1) expression in perivascular macrophages, enabling communication with endothelial cells. Consistently, cMAF deletion in perivascular macrophages causes transcriptional alterations in cerebral arteries, affecting vascular functions. Notably, cMAF emerges as the main transcription factor for human perivascular macrophages, suggesting conservation of this transcriptional module. During Alzheimer's disease (AD), human perivascular macrophages upregulate cMAF and IGF1 to enhance communication with vascular cells, and this response is abrogated in APOE4 carriers. Lastly, we explore an uncharacterized polymorphism in cMAF, providing evidence that the cMAF program is protective against AD. Targeting cMAF in perivascular macrophages may offer new therapeutic strategies for neurodegenerative and cerebrovascular diseases.
    Keywords:  APOE4; Alzheimer's disease; IGF1; arteries; cMAF; cerebral blood flow; cerebrospinal fluid; immune-vascular axis; microglia; perivascular macrophages
    DOI:  https://doi.org/10.1016/j.cell.2026.07.043
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