bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2026–01–25
forty-six papers selected by
Christian Frezza, Universität zu Köln
  1. Acetyl-CoA as a metabolic switch for selective mitophagy.
  2. The Antiseizure Medication Stiripentol Inhibits Mitochondrial Complex I by Blocking Early-Stage Electron Transfer.
  3. Modeling tissue-specific Drosophila metabolism identifies high sugar diet-induced metabolic dysregulation in muscle at reaction and pathway levels.
  4. C3orf33/MISO regulates mitochondrial homeostasis via mitophagy.
  5. Peripheral lysosome levels dictate mTORC1 inactivation even when catabolically impaired.
  6. Chronic stress drives liver cancer by impairing the hepatic kynurenine pathway and immune surveillance.
  7. Silencing lipid catabolism determines longevity in response to fasting.
  8. Heterogeneous sympathetic control of brown adipose tissue.
  9. Past, present and future perspectives on the science of aging.
  10. Cell cycle arrest enhances CD8+ T cell effector function by potentiating glucose metabolism and IL-2 signaling.
  11. Critical role for a high-plasticity cell state in lung cancer.
  12. SLC25A45: a gatekeeper for methylated amino acid metabolism.
  13. Hepatic tryptophan metabolism links chronic stress to liver cancer.
  14. NAD+ and Sirt5 restore mitochondrial bioenergetics failure and improve locomotor defects caused by sucla2 mutations.
  15. PtdIns(3,5)P 2 Is an Endogenous Ligand of STING in Innate Immune Signaling.
  16. Hyperactivation of mTORC1 blocks stem cell fate transitions through TFE3-NuRD association.
  17. Meta-unstable mRNAs in activated CD8+ T cells are defined by interlinked AU-rich elements and m6A mRNA methylation.
  18. Vitamin B12 supports skeletal muscle oxidative phosphorylation capacity in male mice.
  19. ATGL-catalyzed biosynthesis mediates the upregulation of Fatty Acid Hydroxy Fatty Acids (FAHFA) levels in white adipose tissue with fasting.
  20. BCOR mutations define a therapeutic vulnerability to DHODH Inhibition in acute myeloid leukemia.
  21. Fine-tuning the connection between photorespiration and one-carbon metabolism.
  22. Metabolite accumulation mediates the shift between the High Oxygen Consumption and Low Oxygen Consumption phases in the Yeast Metabolic Cycle.
  23. A small molecule VDAC ligand inhibits ERAD and induces selective cancer cell death via disruption of calcium homeostasis.
  24. GMCL1 controls 53BP1 stability and modulates taxane sensitivity.
  25. GDF15 in the tumor microenvironment: A central mediator of cancer immunometabolism and therapeutic resistance.
  26. Palmitic acid induces UCP1-independent mitochondrial depolarization specifcally in brown adipose tissue.
  27. Cell viscosity influences haematogenous dissemination and metastatic extravasation of tumour cells.
  28. Renal Ketogenesis Protects Against Ischemic Kidney Injury.
  29. G9a-mediated H3K9me2 orchestrates intestinal epithelial regeneration through epigenetic silencing of cell cycle-related genes.
  30. Metabolic reprogramming during human neuron differentiation indicates glutaminase as a key determinant in Fragile X syndrome.
  31. Negative Selection Maintains Grossly Altered but Broadly Stable Karyotypes in Metastatic Colorectal Cancer.
  32. Aberrant methylation limits antitumoral inflammation in lung adenocarcinoma by restricting RIPK3 expression.
  33. CRISPR screens in the context of immune selection identify CHD1 and MAP3K7 as mediators of cancer immunotherapy resistance.
  34. A metabolic link between DNA synthesis and chromatin assembly.
  35. Genomic evolution of pancreatic cancer at single-cell resolution.
  36. Spatially controlled induction and regression of basal cell carcinoma, visualized by serial imaging in young and old mice.
  37. Spatiotemporal regulation of energetic charge dictates T cell function.
  38. IL-21 mediates crosstalk between T cells and NK cells during the remission of type 1 diabetes.
  39. The 2025 Sir David Cuthbertson Lecture: Energy metabolism: Beyond calories, feeding the mitochondria.
  40. Stimulator of Interferon Genes Is a Fine-Tuner, but Not a Prime Mover, of Kidney Inflammation.
  41. Distinct sympathetic projections to brown fat regulate thermogenesis and glucose tolerance.
  42. Oxygen-free metabolism in the bird inner retina supported by the pecten.
  43. Macrophage migration inhibitory factor superfamily in tumor metabolism: mechanistic insights and therapeutic potential.
  44. Longitudinal analysis of body weight reveals homeostatic and adaptive traits linked to lifespan in diversity outbred mice.
  45. The lysosomal LAMTOR-Rag complex functions as a checkpoint for antiviral interferon production.
  46. Single-cell atlas of human lung aging identifies cell type dyssynchrony and increased transcriptional entropy.
  1. Autophagy. 2026 Feb;22(2): 235-237
    Acetyl-CoA as a metabolic switch for selective mitophagy.
    Daolin Tang, Rui Kang, Daniel J Klionsky.
      A recent study published in Nature by Zhang et al. reported that cytosolic acetyl-CoA functions as a signaling metabolite that regulates NLRX1-dependent mitophagy during nutrient stress. This discovery reveals a metabolic checkpoint for mitochondrial quality control and provides new insights into KRAS inhibitor resistance.
    Keywords:  Acetyl-CoA; KRAS inhibitor; NLRX1; metabolic signaling; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2025.2593032
  2. J Biol Chem. 2026 Jan 20. pii: S0021-9258(26)00049-9. [Epub ahead of print] 111179
    The Antiseizure Medication Stiripentol Inhibits Mitochondrial Complex I by Blocking Early-Stage Electron Transfer.
    Cyrielle L Bouchez, Thibaut Molinié, Guillaume Duranthon, Sebastian Lillo, Corinne Pellon, Nadia El Mammeri, Benjamin Dartigues, Philippe Pasdois, Benoit Pinson, Macha Nikolski, Anne Devin, Arnaud Mourier, Roland T Ullrich, Thomas Daubon.
      The oxidation of NADH is essential for maintaining cellular redox balance and supporting cell metabolism. Mitochondrial complex I (NADH:ubiquinone oxidoreductase) plays a central role in this process by coupling NADH oxidation to electron transfer and proton translocation across the inner mitochondrial membrane. We previously reported that the antiseizure medication stiripentol decreases lactate production and mitochondrial respiration, suggesting an impact on NADH turnover beyond its known inhibition of lactate dehydrogenase. In this study, we identify complex I as a target of stiripentol across multiple species and cell types. Biochemical and spectroscopic analyses demonstrate that stiripentol inhibits NADH oxidation and electron transfer through a mechanism distinct from that of classical ubiquinone pocket inhibitors such as rotenone or piericidin A. Remarkably, stiripentol acts upstream of the ubiquinone reduction site, representing the first example of a complex I inhibitor with a binding site within the N-module. These findings uncover a previously unrecognized mode of complex I inhibition and link stiripentol's metabolic effects to direct modulation of mitochondrial NADH oxidation. This work broadens the understanding of stiripentol's mechanism of action and highlights its potential to modulate redox metabolism in cancer cells.
    DOI:  https://doi.org/10.1016/j.jbc.2026.111179
  3. Nat Commun. 2026 Jan 19.
    Modeling tissue-specific Drosophila metabolism identifies high sugar diet-induced metabolic dysregulation in muscle at reaction and pathway levels.
    Sun Jin Moon, Yanhui Hu, Monika Dzieciatkowska, Ah-Ram Kim, John M Asara, Angelo D'Alessandro, Norbert Perrimon.
      Individual tissues perform highly specialized metabolic functions to maintain whole-body metabolic homeostasis. Although Drosophila serves as a powerful model for studying human metabolic diseases, modeling tissue-specific metabolism has been limited in this organism. To address this gap, we reconstruct 32 tissue-specific genome-scale metabolic models (GEMs) by integrating a curated Drosophila metabolic network with pseudo-bulk single-nuclei transcriptomics data, revealing distinct metabolic network structures and subsystem coverage across tissues. We validate enriched pathways identified through tissue-specific GEMs, particularly in muscle and fat body, using metabolomics and pathway analysis. Moreover, to demonstrate the utility in disease modeling, we apply muscle-GEM to investigate high sugar diet (HSD)-induced metabolic dysregulation. Constraint-based semi-quantitative flux and sensitivity analyses identify altered NAD(H)-dependent reactions and distributed control of glycolytic flux, including GAPDH. This prediction is further validated through in vivo 13C-glucose isotope tracing study. Notably, decreased glycolytic flux, including GAPDH, is linked to increased redox modifications. Finally, our pathway-level flux analyses identify dysregulation in fructose metabolism. Together, this work establishes a quantitative framework for tissue-specific metabolic modeling in Drosophila, demonstrating its utility for identifying dysregulated reactions and pathways in muscle in response to HSD.
    DOI:  https://doi.org/10.1038/s41467-026-68395-3
  4. Autophagy. 2026 Jan 22.
    C3orf33/MISO regulates mitochondrial homeostasis via mitophagy.
    Jianshuang Li, Wenjun Wang, Li He, Qinghua Zhou.
      Mitochondria maintain homeostasis through dynamic remodeling and stress-responsive pathways, including the formation of specialized subdomains. Peripheral mitochondrial fission generates small MTFP1-enriched mitochondria (SMEM), which encapsulate damaged mtDNA and facilitate its macroautophagic/autophagic degradation. However, the underlying mechanism governing SMEM biogenesis remains unclear. In our recent study, we identified C3orf33/CG30159/MISO as a conserved regulator of mitochondrial dynamics and stress-induced subdomain formation in Drosophila and mammalian cells. C3orf33/MISO is an integral inner mitochondrial membrane (IMM) protein that assembles into discrete subdomains, which we confirm as small MTFP1-enriched mitochondria (SMEM). Mechanistically, C3orf33/MISO promotes mitochondrial fission by recruiting MTFP1 to activate the FIS1-DNM1L pathway while suppressing fusion via OPA1 exclusion. Under basal conditions, MISO is rapidly turned over and contributes to mitochondrial morphology maintenance. Upon specific IMM stresses (e.g. mtDNA damage, OXPHOS dysfunction, cristae disruption), C3orf33/MISO is stabilized, thereby initiating SMEM assembly. These SMEM compartments function as stress-responsive hubs that spatially coordinate IMM reorganization and target damaged mtDNA to the periphery for lysosome-mediated clearance via mitophagy. Together, we address these fundamental gaps by identifying C3orf33/MISO as the key protein that controls SMEM formation to preserve mitochondrial homeostasis under stress.
    Keywords:  Homeostasis; MISO; SMEM; mitochondrial subdomains; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2026.2621110
  5. Cell Commun Signal. 2026 Jan 20.
    Peripheral lysosome levels dictate mTORC1 inactivation even when catabolically impaired.
    Huy Quang Dang, Therése Forssén, Spyridon Pantelios, Aisegkioul Nteli Chatzioglou, Ewa Kurzejamska, C Theresa Vincent, Yasir Ibrahim, Anders P Mutvei.
      The mechanistic target of rapamycin complex 1 (mTORC1) is a central driver of cell growth that is frequently hyperactivated in cancer. While mTORC1 is activated at the lysosomal surface in response to growth factors and amino acids, the processes governing its inactivation are not fully understood. Here, we report that sustained mTORC1 suppression during leucine or arginine starvation requires the translocation of peripheral lysosomes to the perinuclear region. Our data suggest that a pool of mTOR remains active at peripheral lysosomes during starvation, and that increased spatial separation between lysosomes and the plasma membrane attenuates PI3K/Akt signaling-thereby reducing inputs that otherwise maintain mTORC1 activity. Consequently, preventing lysosome translocation and increasing peripheral lysosome levels sustains mTORC1 signaling during prolonged starvation in a PI3K/Akt-dependent manner independently of autophagy. Under these conditions, mTORC1 signaling persists even when lysosomal catabolism is perturbed by chloroquine or concanamycin A. Collectively, these data indicate that the peripheral lysosome pool, even when catabolically impaired, can sustain mTORC1 signaling under nutrient scarcity, by modulating PI3K/Akt signaling input to the pathway. These observations identify peripheral lysosome levels as a critical determinant of mTORC1 inactivation during nutrient stress and may have implications for diseases with aberrant mTORC1 signaling, including cancer.
    Keywords:  Amino acid deprivation; Catabolically impaired lysosomes; Lysosome positioning; MTORC1; PI3K-Akt signaling; Rab7; Rap1
    DOI:  https://doi.org/10.1186/s12964-026-02659-9
  6. Nat Metab. 2026 Jan 19.
    Chronic stress drives liver cancer by impairing the hepatic kynurenine pathway and immune surveillance.
    Renhui Sun, Deyan Jiao, Wenjing Yuan, Hao Wang, Lingtong Ren, Zhendong Fu, Jiaxuan Zhang, Xuetian Yue, Zhuanchang Wu, Chunyang Li, Huili Hu, Jianping Wang, Lifen Gao, Chunhong Ma, Xiaohong Liang.
      Psychological stress is increasingly linked to liver disease, but the underlying mechanisms remain unclear. Here we show that chronic stress disrupts a brain-liver circuit that impairs hepatic CD8+ T cell immunity and accelerates liver cancer progression. Using both oncogene-driven and carcinogen-driven liver cancer models in male mice, we find that psychological stress disrupts catecholamine/β2-adrenergic receptor (ADRB2) signalling, which suppresses the expression of quinolinate phosphoribosyl transferase (QPRT), an enzyme of the kynurenine pathway, in hepatocytes. QPRT loss diverts kynurenine metabolism away from nicotinamide adenine dinucleotide (NAD+) synthesis towards kynurenic acid (KA) accumulation. This shift results in mitochondrial impairment and reduced effector function of liver CD8+ T cells. We confirm that ADRB2/QPRT expression correlates with hepatic NAD+ and KA levels and with CD8+ T cell frequency and function in human liver tissues. Importantly, ADRB2/QPRT overexpression in hepatocytes, or nicotinamide administration, recovers CD8+ T cell function in stressed mice and reduces liver cancer progression. These findings identify a stress-responsive metabolic checkpoint in the liver that links the nervous system to immune surveillance and may be therapeutically targeted in liver cancers.
    DOI:  https://doi.org/10.1038/s42255-025-01430-7
  7. Nat Commun. 2026 Jan 22.
    Silencing lipid catabolism determines longevity in response to fasting.
    Lexus Tatge, Juhee Kim, Rene Solano Fonseca, Kyle Feola, Jordan M Wall, Gupse Otuzoglu, Ann C Johnson, Kielen R Zuurbier, Jaeyoung Oh, Shaghayegh T Beheshti, Victor A Lopez, Anthony J Daley, Emma G Werner, Patrick Metang, Sonja L B Arneaud, Abigail Watterson, Jeffrey G McDonald, Vincent S Tagliabracci, Michael E French, Peter M Douglas.
      Oscillations between lipid anabolism and catabolism are essential for maintaining cellular health during metabolic fluctuations. Fasting, a conserved determinant of aging, improves disease outcomes and extends lifespan, yet the relative contributions of lipid catabolism versus its attenuation to fasting-induced longevity remain unresolved. The metabolic flexibility of C. elegans under variable nutrient availability provides a powerful system to address this question. We show that lifespan extension from fasting depends not on sustained activation of lipid catabolism, but on its silencing upon nutrient replenishment. The fasting-responsive nuclear hormone receptor NHR-49 activates β-oxidation; however, unlike classical ligand-regulated receptors, NHR-49 is regulated through ligand-independent mechanisms involving cofactor-mediated transcriptional attenuation and protein turnover. We identify casein kinase 1 alpha 1 (KIN-19) as a key regulator of metabolic plasticity and fasting-induced longevity that silences β-oxidation via primed phosphorylation of NHR-49. Thus, cooperative ligand-independent silencing of this conserved nuclear hormone receptor promotes fasting-associated longevity.
    DOI:  https://doi.org/10.1038/s41467-026-68764-y
  8. Nat Metab. 2026 Jan 20.
    Heterogeneous sympathetic control of brown adipose tissue.
    Xun Huang, Li Ye.
      
    DOI:  https://doi.org/10.1038/s42255-025-01435-2
  9. Nat Aging. 2026 Jan;6(1): 6-22
    Past, present and future perspectives on the science of aging.
    Fabrisia Ambrosio, Maxim N Artyomov, Steven N Austad, Nir Barzilai, Juan Carlos Izpisua Belmonte, Daniel W Belsky, Bérénice A Benayoun, Anne Brunet, Handan Melike Dönertaş, Dena B Dubal, Evandro F Fang, Jerome N Feige, Linda P Fried, David Furman, Xu Gao, Vadim N Gladyshev, Vera Gorbunova, Myriam Gorospe, Jing-Dong J Han, Oskar Hansson, Eiji Hara, Steve Horvath, Nancy Y Ip, George A Kuchel, Matt Kaeberlein, Dudley W Lamming, Becca R Levy, Guang-Hui Liu, Jinkook Lee, Terrie E Moffitt, Tohru Minamino, Linda Partridge, Parminder Raina, Thomas A Rando, John W Rowe, Michal Schwartz, Andrew J Scott, Felipe Sierra, David A Sinclair, Charlotte E Teunissen, Bruno Vellas, Eric Verdin, Keenan A Walker, Ashley E Webb, Tony Wyss-Coray, Ming Xu, Jin-Tai Yu, Alex Zhavoronkov, Yahyah Aman, Anna Kriebs, Qingzhong Ren, Hannah Walters, Sebastien Thuault.
      
    DOI:  https://doi.org/10.1038/s43587-025-01046-2
  10. Nat Immunol. 2026 Jan 19.
    Cell cycle arrest enhances CD8+ T cell effector function by potentiating glucose metabolism and IL-2 signaling.
    Floortje J van Haften, Tetje C van der Sluis, Hanna S Hepp, Nils Mülling, Reza Nadafi, Bharath Sampadi, Suzanne van Duikeren, J Shirin Mostert, Rosemarijn van der Sterre, Peter A van Veelen, Graham A Heieis, Dominique M B Veerkamp, Thomas H Wesselink, Ward Vleeshouwers, Macha Beijnes, Iris N Pardieck, Eralin L F van Horssen, Anne F de Groot, Manon van der Ploeg, Judith R Kroep, Noel F C C de Miranda, Sabina Y van der Zanden, Jacques Neefjes, Hailiang Mei, Alfred C O Vertegaal, Bart Everts, Sjoerd H van der Burg, Ramon Arens.
      Cell cycle-inhibiting chemotherapeutics are widely used in cancer treatment. Although the primary aim is to block tumor cell proliferation, their clinical efficacy also involves specific effector CD8+ T cells that undergo synchronized proliferation and differentiation. How CD8+ T cells are programmed when these processes are uncoupled, as occurs during cell cycle inhibition, is unclear. Here, we show that activated CD8+ T cells arrested in their cell cycle can still undergo effector differentiation. Cell cycle-arrested CD8+ T cells become metabolically reprogrammed into a highly energized state, enabling rapid and enhanced proliferation upon release from arrest. This metabolic imprinting is driven by increased nutrient uptake, storage and processing, leading to enhanced glycolysis in cell cycle-arrested cells. The nutrient sensible mTORC1 pathway, however, was not crucial. Instead, elevated interleukin-2 production during arrest activates STAT5 signaling, which supports expansion of the energized CD8+ T cells following arrest. Transient arrest in vivo enables superior CD8+ T cell-mediated tumor control across models of immune checkpoint blockade, adoptive cell transfer and therapeutic vaccination. Thus, transient uncoupling of CD8+ T cell differentiation from cell cycle progression programs a favorable metabolic state that supports the efficacy of effector T cell-mediated immunotherapies.
    DOI:  https://doi.org/10.1038/s41590-025-02407-0
  11. Nature. 2026 Jan 21.
    Critical role for a high-plasticity cell state in lung cancer.
    Jason E Chan, Chun-Hao Pan, Jonathan Rub, Gary Guzman, Klavdija Krause, Emma Brown, Zeda Zhang, Hannah Styers, Griffin Hartmann, Zhuxuan Li, Xueqian Zhuang, Scott W Lowe, Doron Betel, Yan Yan, Tuomas Tammela.
      Plasticity-the ability of cells to undergo phenotypic transitions-drives cancer progression and therapy resistance1-3. Recent studies have suggested that plasticity in solid tumours is concentrated in a minority subset of cancer cells4-6, yet functional studies examining this high-plasticity cell state (HPCS) in situ are lacking. Here we develop mouse models enabling the detection, longitudinal lineage tracing and ablation of the HPCS in autochthonous lung tumours in vivo. Lineage tracing reveals that the HPCS cells possess a high capacity for cell state transitions, giving rise to both early neoplastic (differentiated) and progressed lung cancer cell states in situ. Longitudinal lineage tracing using secreted luciferases reveals that HPCS-derived cells have a high capacity for growth compared with bulk cancer cells or another cancer cell state with features of differentiated lung epithelium. Ablation of HPCS cells in early neoplasias abrogates benign-to-malignant transition, whereas ablation in established tumours by suicide gene or chimeric antigen receptor (CAR) T cells robustly reduces tumour burden. We further demonstrate that the HPCS gives rise to therapy-resistant cell states, whereas HPCS ablation suppresses resistance to chemotherapy and oncoprotein-targeted therapy. Notably, an HPCS-like state is ubiquitous in regenerating epithelia and in carcinomas of multiple other tissues, revealing a convergence of plasticity programs. Our work establishes the HPCS as a critical hub enabling reciprocal transitions between cancer cell states. Targeting the HPCS in lung cancer and in other carcinomas may suppress cancer progression and eradicate treatment resistance.
    DOI:  https://doi.org/10.1038/s41586-025-09985-x
  12. Trends Endocrinol Metab. 2026 Jan 22. pii: S1043-2760(25)00283-8. [Epub ahead of print]
    SLC25A45: a gatekeeper for methylated amino acid metabolism.
    Yue Zhang, Yan Tian, Xianghui Fu.
      The metabolite substrates of numerous transporters remain largely elusive. Two recent studies by Khan et al. and Dias et al. identify SLC25A45 as a mitochondrial transporter of methylated amino acids that supports de novo carnitine synthesis, providing a valuable strategy for deorphanizing transporters and novel insights into cytoplasm-mitochondria communication and metabolic coordination.
    Keywords:  carnitine biosynthesis; fasting; machine learning; mitochondria; trimethyllysine
    DOI:  https://doi.org/10.1016/j.tem.2025.12.005
  13. Nat Metab. 2026 Jan 19.
    Hepatic tryptophan metabolism links chronic stress to liver cancer.
    Gerard Clarke, Lily Keane, John F Cryan.
      
    DOI:  https://doi.org/10.1038/s42255-025-01446-z
  14. JCI Insight. 2026 Jan 23. pii: e181812. [Epub ahead of print]11(2):
    NAD+ and Sirt5 restore mitochondrial bioenergetics failure and improve locomotor defects caused by sucla2 mutations.
    Joy Richard, Giulia Lizzo, Noélie Rochat, Adrien Jouary, Pedro Tm Silva, Alice Parisi, Stefan Christen, Sofia Moco, Michael B Orger, Philipp Gut.
      Mitochondria-derived acyl-coenzyme A (acyl-CoA) species chemically modify proteins, causing damage when acylation reactions are not adequately detoxified by enzymatic removal or protein turnover. Defects in genes encoding the mitochondrial respiratory complex and TCA cycle enzymes have been shown to increase acyl-CoA levels due to reduced enzymatic flux and result in proteome-wide hyperacylation. How pathologically elevated acyl-CoA levels contribute to bioenergetics failure in mitochondrial diseases is not well understood. Here, we demonstrate that bulk succinylation from succinyl-CoA excess consumes the enzymatic cofactor NAD+ and propagates mitochondrial respiratory defects in a zebrafish model of succinyl-CoA ligase deficiency, a childhood-onset encephalomyopathy. To explore this mechanism as a therapeutic target, we developed a workflow to monitor behavioral defects in sucla2-/- zebrafish and show that hypersuccinylation is associated with reduced locomotor behavior and impaired ability to execute food hunting patterns. Postembryonic NAD+ precursor supplementation restores NAD+ levels and improves locomotion and survival of sucla2-/- zebrafish. Mechanistically, nicotinamide and nicotinamide riboside require the NAD+-dependent desuccinylase Sirt5 to enhance oxidative metabolism and nitrogen elimination through the urea cycle. Collectively, NAD+ supplementation activates Sirt5 to protect against damage to mitochondria and locomotor circuits caused by protein succinylation.
    Keywords:  Cell biology; Genetic diseases; Metabolism; Mitochondria
    DOI:  https://doi.org/10.1172/jci.insight.181812
  15. bioRxiv. 2025 Dec 29. pii: 2025.12.29.696917. [Epub ahead of print]
    PtdIns(3,5)P 2 Is an Endogenous Ligand of STING in Innate Immune Signaling.
    Jay Xiaojun Tan, Bo Lv, Jie Li, Tuo Li, Fenghe Du, Xiang Chen, Xuewu Zhang, Xiao-Chen Bai, Zhijian J Chen.
      Cytosolic DNA exposure triggers innate immune responses through cyclic GMP-AMP (cGAMP) synthase (cGAS) 1-3 . Upon binding to DNA, cGAS is activated to produce cGAMP, which functions as a second messenger that binds to stimulator of interferon genes (STING), an endoplasmic reticulum (ER)-localized signaling adaptor 3-5 . STING then traffics from the ER to the Golgi, leading to activation of the kinases TBK1 and IKK and subsequent induction of interferons and other cytokines 6-10 . Here we show that phosphatidylinositol 3,5-bisphosphate [PtdIns(3,5)P 2 ] is an endogenous ligand of STING that functions together with cGAMP to induce STING activation. Proteomics analysis identified a constitutive interaction between STING and PIKfyve, an enzyme that produces PtdIns(3,5)P 2 in mammalian cells. Deletion of PIKfyve blocked STING trafficking from the ER and TBK1 activation. In vitro reconstitution revealed a strong and selective effect of PtdIns(3,5)P 2 on STING activation. Purified STING bound directly to PtdIns(3,5)P 2 in a fluorescence resonance energy transfer (FRET) assay. Consistently, PtdIns(3,5)P 2 promoted cGAMP-induced STING oligomerization by binding to a groove between STING dimers as revealed by cryo-EM (Li et al., co-submitted). Similar to PIKfyve depletion, mutation of the PtdIns(3,5)P 2 -binding residues in STING blocked its trafficking and downstream signaling. These results reveal PtdIns(3,5)P 2 as a lipid ligand of STING with essential roles in innate immunity.
    DOI:  https://doi.org/10.64898/2025.12.29.696917
  16. EMBO Rep. 2026 Jan 20.
    Hyperactivation of mTORC1 blocks stem cell fate transitions through TFE3-NuRD association.
    Peizhi Li, Shuhui Xu, Xinyu Wu, Yin Gao, Tanveer Ahmed, Yinghua Huang, Dajiang Qin, Baoming Qin, Lulu Wang, Xueting Xu.
      Mechanistic target of rapamycin complex 1 (mTORC1) integrates signals from nutrients, growth factors, and cellular stress to regulate biosynthesis and maintain homeostasis. Dysregulated mTORC1 disrupts stem cell homeostasis and impairs cell fate transitions in vivo and in vitro. Previous studies have shown that mTORC1 hyperactivation promotes nuclear translocation of TFE3, blocking pluripotency exit in both mouse and human naïve embryonic stem cells. Similarly, our earlier work has demonstrated that sustained mTORC1 activation impedes somatic cell reprogramming via the transcriptional coactivator PGC1α. This raises the question of how mTORC1 coordinates gene transcription across distinct transitions in pluripotent cells. Here, we show that TFE3 mediates the transcriptional blockade induced by mTORC1 hyperactivation during reprogramming. Notably, during both pluripotency exit and reprogramming, TFE3 recruits the NuRD corepressor complex to repress genes essential for cell fate transitions. These findings uncover a shared mechanism by which mTORC1 and TFE3 regulate stem cell identity, highlighting the dual regulatory role of TFE3 and its potential implications in development, aging, and tumorigenesis.
    Keywords:  NuRD Complex; Pluripotency Exit; Somatic Cell Reprogramming; TFE3; mTORC1
    DOI:  https://doi.org/10.1038/s44319-025-00544-z
  17. Nat Commun. 2026 Jan 22. 17(1): 160
    Meta-unstable mRNAs in activated CD8+ T cells are defined by interlinked AU-rich elements and m6A mRNA methylation.
    Paulo A Gameiro, Iosifina P Foskolou, Yumna A Butt, Aniek A M Martens, Klara Kuret Hodnik, Igor Ruiz de Los Mozos, Nordin D Zandhuis, Žan Hozjan, Veronica M Kot, Rupert Faraway, Michiel Vermeulen, Monika C Wolkers, Randall S Johnson, Jernej Ule.
      CD8+ T cells can rapidly produce effector molecules following activation. This activation triggers rapid changes in gene expression that rely on the control of mRNA levels via multiple mechanisms, including RNA modifications. N6-methyladenosine (m6A) is an abundant post-transcriptional modification that promotes the decay of messenger RNAs in the cytosol. However, how recognition of m6A sites is integrated with other regulatory mechanisms that alter the fate of immunoregulatory mRNAs in CD8+ T cells remains unexplored. Here, we apply the m6A-iCLIP and GLORI methods to identify the importance of m6A sites flanked by AU-rich elements (AREs) within the 3'UTRs of CD8+ T cell mRNAs. Presence of such ARE-flanking m6A motifs predicts meta-unstable mRNAs that rapidly decay upon CD8+ T cell activation. We demonstrate interdependent effects of mutations in the identified AREs and RRACHs on TNF mRNA stability. The ARE-flanking m6A sites in these mRNAs show particularly high iCLIP crosslinking of YTHDF proteins, which are also identified by proteomic interactome analyses along with additional novel RNA-binding proteins. Our study reveals a crosstalk between m6A and ARE-dependent mechanisms in CD8+ T cells, providing new approaches for modulating mRNA decay in T cell activation.
    DOI:  https://doi.org/10.1038/s41467-025-67762-w
  18. J Nutr. 2026 Jan 20. pii: S0022-3166(26)00016-7. [Epub ahead of print] 101367
    Vitamin B12 supports skeletal muscle oxidative phosphorylation capacity in male mice.
    Luisa F Castillo, Katarina E Heyden, Abigail R Williamson, Wenxia Ma, Olga V Malysheva, Nathaniel M Vacanti, Anna E Thalacker-Mercer, Martha S Field.
       BACKGROUND: Vitamin B12 is a cofactor in folate-mediated one-carbon metabolism (FOCM), which generates nucleotides (thymidylate (dTMP) and purines) and methionine. Depressed de novo thymidylate (dTMP) synthesis leads to uracil accumulation in DNA.
    OBJECTIVE: The purpose of this study was to determine how B12 availability affects mitochondrial DNA (mtDNA) integrity and mitochondrial function in skeletal muscle. B12 deficiency was modeled in young-adult mice. Intramuscular B12 injection in aged mice assessed the role of B12 supplementation in age-related changes in skeletal muscle.
    METHODS: Male methionine synthase knockdown (Mtr+/-) and wild-type littermates (Mtr+/+) were weaned to either an AIN93G-based control (C) diet containing 25 μg/kg vitamin B12 (Mtr+/+, n=8; Mtr+/-, n=9) or a B12-deficient (-B12) diet containing 0 μg/kg vitamin B12 (n=9 per genotype) for seven weeks. Aged (20-22mo) male C57BL/6N mice were acclimated to an AIN93G control diet four weeks, then received either weekly injections of saline (vehicle control [30 uL 0.9% NaCl], n=5) or B12 (0.65 μg per 30uL 0.9% NaCl; n=6) in each of two hindleg muscles [1.25 μg B12 total]) for eight weeks. Outcomes measured included maximal oxygen consumption rate (OCR), uracil in mtDNA (a biomarker of mtDNA integrity), mtDNA copy number, and mitochondrial mass. Data were analyzed using a two-way ANOVA in the Mtr+/- mouse model exposed to B12-deficient diets and by a student's t-test for B12 supplementation in aged mice.
    RESULTS: The tibialis anterior (TA) muscle from Mtr+/- mice exhibited 50% lower (p=0.01) maximal respiratory capacity of the electron transport chain than did TA from Mtr+/+ mice. Exposure to the -B12 diet lowered maximal capacity of complex I in mitochondrially rich muscle (soleus and mitochondria-rich portions of quadriceps and gastrocnemius) by 25% (p=0.02). Uracil in mitochondrial DNA (mtDNA) in red muscle and gastrocnemius was elevated ∼10 fold with exposure to -B12 diet (p=0.04 and p<0.001, respectively). In aged mice, gastrocnemius complex IV activity was increased 2-fold with intramuscular B12 supplementation (p=0.04).
    CONCLUSIONS: Exposure to a B12-deficient diet led to uracil accumulation in mtDNA and impaired maximal oxidative capacity in skeletal muscle. B12 supplementation improved complex IV maximal capacity in gastrocnemius from aged mice, a model of age-related skeletal muscle decline.
    Keywords:  Vitamin B12; mitochondrial DNA; oxidative phosphorylation; skeletal muscle; thymidylate; uracil
    DOI:  https://doi.org/10.1016/j.tjnut.2026.101367
  19. J Biol Chem. 2026 Jan 20. pii: S0021-9258(26)00039-6. [Epub ahead of print] 111169
    ATGL-catalyzed biosynthesis mediates the upregulation of Fatty Acid Hydroxy Fatty Acids (FAHFA) levels in white adipose tissue with fasting.
    Anna Santoro, Zhenlong Chen, Andrew T Nelson, Dionicio Siegel, Barbara B Kahn.
      FAHFAs are a family of bioactive lipids. A subclass of these, Palmitic Acid Hydroxy Stearic Acids (PAHSAs) have anti-inflammatory and anti-diabetic effects. Adipose tissue PAHSA levels are upregulated with increased de novo lipogenesis and fasting, and downregulated with insulin resistance and obesity. Adipose Triglyceride Lipase (ATGL) regulates FAHFAs through two distinct mechanisms: hydrolysis of triacylglycerol (TG)-containing FAHFAs and catalyzing formation of the ester bond found in all FAHFAs through a transacylase reaction. ATGL mediates the increase of PAHSAs with fasting in white adipose tissue (WAT), but the mechanism for this has not been determined. Here, we show that multiple FAHFAs are dynamically regulated with fasting and short-term refeeding in both perigonadal (PG) and subcutaneous (SQ) WAT due to ATGL transacylase activity. Our in vivo studies with stable isotopes demonstrate that de novo FAHFA synthesis is upregulated with fasting. This observation along with the fact that FAHFA-TGs are unchanged (SQ WAT) or increased (PG WAT) with fasting and FAHFA hydrolysis is unchanged, suggests that the primary mechanism by which FAHFAs increase in WAT with fasting is de novo synthesis. Using adipose tissue-specific ATGL knock out mice, we show that ATGL is required for the fasting-induced upregulation of endogenous levels and de novo synthesis of multiple FAHFAs. Altogether, this study shows that fasting upregulates multiple FAHFAs by increasing ATGL-mediated synthesis of FAHFAs, inferring that fasting, a physiologic state that is classically known to activate the lipase activity of ATGL, also stimulates its transacylase activity.
    Keywords:  ATGL-KO mice; FAHFA; Hydroxy Stearic Acids; PAHSA; TG-FAHFA; adipose tissue metabolism; adipose triglyceride lipase (ATGL); lipid metabolism; lipid synthesis; triglyceride
    DOI:  https://doi.org/10.1016/j.jbc.2026.111169
  20. Ann Hematol. 2026 Jan 19. 105(1): 32
    BCOR mutations define a therapeutic vulnerability to DHODH Inhibition in acute myeloid leukemia.
    Florian Robert, Cherif Badja, Soraya Boushaki, Andrea Degasperi, Yasin Memari, Sophie Momen, Theodoros I Roumeliotis, Zuza Kozik, Malgorzata Gozdecka, Jyoti Choudhary, George Vassiliou, Gene Cc Koh, Serena Nik-Zainal.
      Acute Myeloid Leukemia (AML) remains challenging to treat, especially in cases with mutations in the BCL-6 co-repressor (BCOR), which are associated with poor prognosis and chemo-resistance. In this study, we reveal a synthetic lethal interaction between BCOR and dihydroorotate dehydrogenase (DHODH). We demonstrate that BCOR-deficient cells have a heightened sensitivity to DHODH inhibitors such as brequinar and leflunomide, that are already in clinical use. We confirm that DHODH inhibition selectively induces cell death in BCOR-mutant cells in multiple cellular models, in malignant and non-malignant cells, through chemical and genetic manipulation. Interestingly, we find that the dependency on DHODH does not stem from its role in de novo pyrimidine biosynthesis disruption. Rather, DHODH's role in the electron transport chain, essential for mitigating reactive oxygen species, may be the physiological vulnerability that pushes BCOR-mutant cells toward cell death when DHODH is inhibited. DHODH inhibitors could be repurposed as targeted therapies for BCOR-mutant tumors, offering a promising strategy for precision medicine in AML and other cancers.
    Keywords:  Acute myeloid leukemia; BCOR; DHODH; DHODH inhibition; Leukemia; Synthetic lethality; Targeted therapy 
    DOI:  https://doi.org/10.1007/s00277-026-06773-z
  21. Trends Biochem Sci. 2026 Jan 19. pii: S0968-0004(25)00297-X. [Epub ahead of print]
    Fine-tuning the connection between photorespiration and one-carbon metabolism.
    Welder Alves da Silva, Auxiliadora Oliveira Martins, Moab Torres de Andrade, Wagner Luiz Araújo.
      Recent advances have highlighted the flexibility of the plant metabolic network to meet its requirements under specific environmental and physiological conditions. In their publication, Gashu et al. provided a more complete picture of how much photosynthetically assimilated carbon is channeled from photorespiration to one-carbon metabolism under different photorespiratory conditions.
    Keywords:  carbon flux; cytosolic C(1) metabolism; metabolic flexibility; metabolic network; noncanonical metabolism; photorespiratory serine metabolism
    DOI:  https://doi.org/10.1016/j.tibs.2025.12.005
  22. bioRxiv. 2025 Dec 02. pii: 2025.12.01.691504. [Epub ahead of print]
    Metabolite accumulation mediates the shift between the High Oxygen Consumption and Low Oxygen Consumption phases in the Yeast Metabolic Cycle.
    Salvador Casani-Galdon, Shidong Xi, Jane Mellor, Sonia Tarazona, Ana Conesa.
      The Yeast Metabolic Cycle (YMC) is a molecular system that serves as a model to study the internal clock that maintains homeostasis in complex organisms. Traditionally, this ultradian rhythm has been studied in the three phases where mature mRNA transcripts show peak accumulation. However, recent studies have shown that the YMC can be interpreted as a two-phase cycle based on altered redox states, known as the high (HOC) and low oxygen consumption (LOC) phases. The length of the HOC phase is fixed and its frequency is nutrient dependent but the nature of the HOC to LOC transition is poorly defined. Here, we use multivariate statistics to integrate metabolic, chromatin and transcriptional changes across the YMC to study the levels of organization that connect them. Our model reveals that both the HOC-LOC and LOC-HOC phase transitions in the YMC are coordinated by accumulating metabolites, reflecting cellular energetics and redox state. We propose that the cycling behavior of chromatin states, transcription and transcripts is a consequence of accumulating metabolites at phase transitions, which function by modulating protein activity and coordinating biochemical pathways to maintain cellular homeostasis.
    DOI:  https://doi.org/10.64898/2025.12.01.691504
  23. Nat Commun. 2026 Jan 17.
    A small molecule VDAC ligand inhibits ERAD and induces selective cancer cell death via disruption of calcium homeostasis.
    Wenjing Yan, Daniel C Talley, Antara Syam, Carina Danchik, Yongwang Zhong, Xianzheng Zhang, Xiaoying Liu, Bolormaa Baljinnyam, Stephen C Kales, Matthew G Cyr, Yuhong Fang, Alexey V Zakharov, Xin Hu, Taylor Niehoff, Tuan Xu, Yanyan Qu, Allison Yang, Valentine V Courouble, Qin Yao, Anton Simeonov, Ruili Huang, Tatiana K Rostovtseva, Sergey M Bezrukov, Christopher A LeClair, Josephine M Egan, Hua Wang, Dingyin Tao, Ganesha Rai, Mark J Henderson, Shengyun Fang.
      Endoplasmic reticulum-associated degradation (ERAD) is a critical protein quality control mechanism that also regulates lipid metabolism and calcium homeostasis. Dysregulation of ERAD and unfolded protein response underlies diseases including cancer, neurodegenerative disorders, and metabolic syndromes. Small molecule modulators of ERAD could enable mechanistic discovery and therapeutic intervention, but few have been identified. Using a high-content screening, we discovered several ERAD-modulating compounds, including NCATS-SM0225, an ERAD inhibitor that unexpectedly binds all three isoforms of VDAC, outer mitochondrial membrane proteins enriched at mitochondria-associated membranes. This led us to discover an essential role for VDACs in ERAD and ER-phagy. NCATS-SM0225 elevates cytosolic, ER, and mitochondrial calcium through calcium influx and IP3R-MCU activity. This calcium imbalance strengthens VDAC1-IP3R coupling and activates PERK, which phosphorylates STIM1 and drives degradation of key ERAD regulators. Loss of these components amplifies PERK signaling and selectively kills cancer cells while sparing normal cells. These findings uncover a cancer-specific role of VDACs in ERAD regulation and calcium signaling, highlighting a therapeutically actionable vulnerability.
    DOI:  https://doi.org/10.1038/s41467-025-67816-z
  24. Elife. 2026 Jan 19. pii: RP106730. [Epub ahead of print]14
    GMCL1 controls 53BP1 stability and modulates taxane sensitivity.
    Yuki Kito, Tania J González-Robles, Sharon Kaisari, Juhee Pae, Sheena Faye Garcia, Juliana Ortiz-Pacheco, Beatrix Ueberheide, Antonio Marzio, Gergely Róna, Michele Pagano.
      Mitotic surveillance pathways monitor the duration of mitosis (M phase) in the cell cycle. Prolonged M phase, caused by spindle attachment defects or microtubule-targeting drugs, triggers formation of the ternary 'mitotic stopwatch pathway' complex (MSP) consisting of 53BP1, USP28, and p53. This complex stabilizes p53, leading to cell cycle arrest or apoptosis in daughter cells. In cancers that are resistant to paclitaxel, a microtubule-targeting agent, cells bypass mitotic surveillance activation, allowing unchecked proliferation, although the underlying mechanisms remain poorly understood. Here, we identify GMCL1 as a key negative regulator of MSP signaling. We show that 53BP1 physically interacts with GMCL1, but not its paralog GMCL2, and we map their interaction domains. CRL3GMCL1 functions as a ubiquitin ligase that targets 53BP1 for degradation during the M phase, thereby reducing p53 accumulation in daughter cells. Depletion of GMCL1 inhibits cell cycle progression upon release from prolonged mitotic arrest, a defect that is rescued by co-silencing 53BP1 or USP28. Moreover, GMCL1 depletion sensitizes cancer cells to paclitaxel in a p53-dependent manner. Together, our findings support a model in which dysregulated CRL3GMCL1-mediated degradation of 53BP1 prevents proper MSP function, leading to p53 degradation and continued proliferation. Targeting GMCL1 may, therefore, represent one possible avenue for addressing paclitaxel resistance in cancer cells with functional p53.
    Keywords:  53BP1; GMCL1; cancer biology; cell biology; human; mitotic stopwatch; p53; prolonged mitosis; protein degradation
    DOI:  https://doi.org/10.7554/eLife.106730
  25. Cytokine Growth Factor Rev. 2026 Jan 13. pii: S1359-6101(26)00004-3. [Epub ahead of print]88 47-57
    GDF15 in the tumor microenvironment: A central mediator of cancer immunometabolism and therapeutic resistance.
    Lingeng Lu, Caroline H Johnson, Sajid A Khan, Melinda L Irwin.
      Growth differentiation factor 15 (GDF15), a divergent member of the transforming growth factor-β (TGFβ) superfamily, has emerged as a pivotal cytokine linking cancer metabolism, immune suppression, and systemic energy balance. Initially characterized as a stress-induced cytokine with roles in appetite regulation and cachexia, GDF15 was first identified in activated macrophages and is also secreted by tumor cells, stromal cells and stressed epithelial cells across multiple tissues. Functionally, GDF15 exerts pleiotropic effects on both immune and nonimmune cell populations, modulating T cells, dendritic cells, and macrophages in the tumor microenvironment (TME), and metabolic tissues such as liver, adipose and muscle, thereby promoting tumor progression, therapeutic resistance, and cancer-associated metabolic dysregulation. In several human cancers of such as colorectal, pancreatic, breast and brain, elevated GDF15 levels correlate with poor prognosis, immune evasion, and chemoresistance. Mechanistically, GDF15 modulates fatty acid metabolism, promotes epithelial-mesenchymal transition, and suppresses anti-tumor immunity by impairing dendritic cell maturation and excluding CD8+ T cell infiltration. Targeting GDF15 may reprogram immunometabolic suppression and enhance checkpoint blockade efficacy. This review synthesizes current knowledge on GDF15's multifaceted roles in tumor biology, emphasizing its function as a central node of cancer immunometabolism. We highlight advances in spatial multi-omics, integrating transcriptomics and immune imaging, that reveal GDF15 spatially restricted immunosuppression in the tumor microenvironment.
    Keywords:  Cancer immunotherapy; Colorectal cancer; GDF15; Immunometabolism; Obesity; Pancreatic cancer; Spatial metabolomics; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.cytogfr.2026.01.004
  26. J Biol Chem. 2026 Jan 20. pii: S0021-9258(26)00047-5. [Epub ahead of print] 111177
    Palmitic acid induces UCP1-independent mitochondrial depolarization specifcally in brown adipose tissue.
    Yuto Ishikawa, Isshin Shiiba, Eisho Kozakura, Haruto Yabu, Shun Hirose, Hijiri Oshio, Ken-Ichi Yamada, Yuko Okamatsu-Ogura, Ryoko Inatome, Shigeru Yanagi.
      Brown adipose tissue (BAT) is a major site of non-shivering thermogenesis, where mitochondria generate heat instead of adenosine triphosphate (ATP). The thermogenesis occurs through the activity of uncoupling protein 1 (UCP1) which specifically resides in the mitochondrial inner membrane and dissipates the mitochondrial proton gradient upon activation by long-chain free fatty acids (FFA). Although UCP1-independent proton leak has been reported, the mechanism underlying UCP1-independent mitochondrial membrane depolarization remains largely unknown. Here, using primary brown adipocytes, we found that cold-mimicking stimulation induces mitochondrial membrane depolarization even under UCP1 knockout and knockdown conditions. Furthermore, during cold-mimicking stimulation, palmitic acid shows the most prominent increase in a lipolysis-dependent manner. Notably, palmitic acid directly decreases mitochondrial membrane potential specifically in mitochondria isolated from BAT, but not in those isolated from liver or brain. These findings suggest that palmitic acid contributes to mitochondrial depolarization in BAT, thereby contributing to UCP1-independent depolarization.
    Keywords:  Brown adipose tissue; Mitochondria; Palmitic acid; UCP1-independent mitochondrial depolarization
    DOI:  https://doi.org/10.1016/j.jbc.2026.111177
  27. Nat Mater. 2026 Jan 19.
    Cell viscosity influences haematogenous dissemination and metastatic extravasation of tumour cells.
    Valentin Gensbittel, Zeynep Yesilata, Louis Bochler, Gautier Follain, Laurie Nemoz-Billet, Olivier Lefebvre, Klemens Uhlmann, Annabel Larnicol, Giulia E M Ammirati, Sébastien Harlepp, Ruchi Goswami, Salvatore Girardo, Laetitia Paulen, Vincent Hyenne, Vincent Mittelheisser, Tristan Stemmelen, Anne Molitor, Raphael Carapito, Guillaume Belthier, Julie Pannequin, Martin Kräter, Daniel J Müller, Daniel Balzani, Jochen Guck, Naël Osmani, Jacky G Goetz.
      Metastases arise from a multistep process during which tumour cells face several microenvironmental mechanical challenges, which influence metastatic success. However, how circulating tumour cells (CTCs) adapt their mechanics to such microenvironments is not fully understood. Here we report that the deformability of CTCs affects their haematogenous dissemination and identify mechanical phenotypes that favour metastatic extravasation. Combining intravital microscopy with CTC-mimicking elastic beads, mechanical tuning in tumour lines and profiling of tumour-patient-derived cells, we demonstrate that the inherent mechanical properties of circulating objects dictate their ability to enter constraining vessels. We identify cellular viscosity as a rheostat of CTC circulation and arrest, and show that cellular viscosity is crucial for efficient extravasation. Moreover, we find that mechanical properties that favour extravasation and subsequent metastatic outgrowth can be opposite. Altogether, our results establish CTC viscosity as a key biomechanical parameter that shapes several steps of metastasis.
    DOI:  https://doi.org/10.1038/s41563-025-02462-w
  28. J Am Soc Nephrol. 2026 Jan 21.
    Renal Ketogenesis Protects Against Ischemic Kidney Injury.
    Kyle Feola, Andrea H Venable, Mina Rasouli, Emma-Grace Haley, Chetana Jadhav, Ricardo Monroy, Tatyana McCoy, Sarah C Huen.
       BACKGROUND: Abnormal renal fatty acid oxidation in kidney disease suggests that dysregulated metabolism is a key component of kidney disease pathogenesis. While the liver is the main ketogenic organ, the rate-limiting enzyme for ketogenesis, mitochondrial Hydroxymethylglutaryl-CoA synthase 2 (HMGCS2), is induced in the proximal tubule of the kidney during fasting. We previously demonstrated that HMGCS2 induced in the kidney does not contribute to the circulating pool of ketones during fasting and cannot compensate for hepatic ketogenic deficiency. We hypothesized that kidney HMGCS2 may be acting locally within the kidney to maintain normal function during metabolic stress or injury.
    METHODS: Mice with kidney or liver specific deletion of Hmgcs2 were subjected to ischemia/reperfusion injury (IRI). Kidney histology, metabolomics and lipidomics were analyzed. Mice were placed on a ketogenic diet for four days to increase plasma and kidney ketone content. Using novel mouse models with proximal tubular hemagglutinin-tagged mitochondria with or without Hmgcs2 deletion, proximal tubular-specific mitochondria were isolated and fatty acid oxidation capacity was measured after IRI.
    RESULTS: Mice with kidney specific Hmgcs2 deletion had significantly more kidney injury after IRI compared to wild-type controls. Kidneys lacking HMGCS2 exhibited a decrease in ketone content and an increase in lipid droplet accumulation after IRI. Proximal tubular-specific mitochondria lacking HMGCS2 had significantly lower fatty acid oxidation capacity both at baseline and after ischemic injury. Administration of a ketogenic diet for four days prior to IRI was sufficient to decrease kidney injury and augment mitochondrial fatty acid oxidation in kidney Hmgcs2 knockout mice. Kidney tissue lipidomics revealed that the loss of kidney HMGCS2 was associated with a decrease in both arachidonic acid containing phospholipids and prostaglandin levels.
    CONCLUSIONS: Loss of renal HMGCS2 and resultant ketogenesis increased ischemia-induced injury and decreased mitochondrial fatty acid oxidation capacity, suggesting a role in renal ketogenesis in limiting acute kidney injury.
    DOI:  https://doi.org/10.1681/ASN.0000001014
  29. Nat Commun. 2026 Jan 19.
    G9a-mediated H3K9me2 orchestrates intestinal epithelial regeneration through epigenetic silencing of cell cycle-related genes.
    Jingzhou Chen, Xiaoliang Shi, Xinyi Zhou, Ju Huang, Linghao Xia, Zhen Hu, Jiaji Gu, Xiaole Sheng, Xiaolong Ge, Xudong Fu, Qian Xiao, Wei Zhou, Rongpan Bai, Zhengping Xu, Jinghao Sheng.
      Histone modifications play an important role in intestinal homeostasis and regeneration. Here, we identify histone H3 lysine 9 di-methylation (H3K9me2) as an epigenetic regulator of intestinal epithelial repair through mass spectrometry-based screening of histone modifications. We then find that H3K9me2 and its methyltransferase G9a levels are reduced during acute injury and progressively increase during regeneration in both mouse models and human clinical samples. Genetic ablation of G9a in intestinal epithelial cells or pharmacological inhibition of its enzymatic activity substantially impairs intestinal regeneration and reduces survival following irradiation. Mechanistically, integrative genomic analyses reveal that G9a-mediated H3K9me2 suppresses chromatin accessibility and transcriptional activity of cell cycle arrest genes, including Rb1cc1, Rb1, Cdkn1a, and Pten, thereby promoting intestinal stem cell proliferation. Furthermore, we elucidate that IL-4-STAT6 signaling controls G9a expression during regeneration, i.e., IL-4 upregulation leads to STAT6 phosphorylation and subsequent transcriptional activation of G9a. These findings establish the IL-4-STAT6-G9a-H3K9me2 regulatory axis as a critical epigenetic mechanism controlling intestinal regeneration with therapeutic potential for gastrointestinal disorders.
    DOI:  https://doi.org/10.1038/s41467-026-68626-7
  30. Cell Rep. 2026 Jan 19. pii: S2211-1247(25)01629-8. [Epub ahead of print]45(1): 116857
    Metabolic reprogramming during human neuron differentiation indicates glutaminase as a key determinant in Fragile X syndrome.
    Sneha Shah, Daniel Barnes, Botao Liu, Tenzin Tseyang, Thang Do, Jodi L Bubenik, Suna Jung, Mina N Anadolu, Maria P Ivshina, Verónica Martínez-Cerdeño, Elizabeth Berry-Kravis, Maurice S Swanson, Jessica B Spinelli, Joel D Richter.
      Metabolic homeostasis gone awry is a contributor to, if not an underlying cause of, several neurologic disorders. Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by a trinucleotide repeat expansion in FMR1 and consequent loss of the encoded protein FMRP, which results in downstream molecular, neurologic, and mitochondrial deficits that are linked to cognitive impairment. In the human postmortem brain, many metabolites and solute carrier proteins are coordinately dysregulated, which also occurs during the differentiation of human induced pluripotent stem cells (iPSCs) into excitatory neurons. Metabolic tracing in FXS neurons demonstrates a dearth of glutamine deamidation to glutamate, which reduces anaplerosis into the TCA cycle, potentially hindering the bioenergetic and biosynthetic functions of mitochondria. Mechanistically, aberrant expression of glutaminase isoforms in FXS is responsible for reduced glutaminolysis, thereby altering glutamate levels, which may contribute to FXS.
    Keywords:  CP: metabolism; CP: neuroscience; Fragile X syndrome; glutamate transporters; glutaminase; human neurons; iPSC; metabolomics
    DOI:  https://doi.org/10.1016/j.celrep.2025.116857
  31. Cancer Discov. 2026 Jan 21. OF1-OF17
    Negative Selection Maintains Grossly Altered but Broadly Stable Karyotypes in Metastatic Colorectal Cancer.
    William C H Cross, Salpie Nowinski, George D Cresswell, Maximilian Mossner, Abhirup Banerjee, Bingxin Lu, Marc J Williams, Georgios Vlachogiannis, Laura J Gay, Ann-Marie Baker, Christopher Kimberley, Frederick J H Whiting, Hayley L Belnoue-Davis, Pierre Martinez, Maria Traki, Viola Walther, Kane Smith, Javier Fernandez-Mateos, Erika Yara-Romero, Erica A Oliveira, Salvatore Milite, Giulio Caravagna, Chela T James, George Elia, Alison Berner, Chang-Ho Ryan Choi, Pradeep Ramagiri, Ritika Chauhan, Nik Matthews, Jamie Murphy, Anthony Antoniou, Susan K Clark, Miriam Mitchison, Jo-Anne Chin Aleong, Enric Domingo, Inmaculada Spiteri, Stuart A C McDonald, Darryl Shibata, Miangela M Laclé, Lai Mun Wang, Morgan Moorghen, Ian P M Tomlinson, Marco Novelli, Marnix Jansen, Alan Watson, Nicola Valeri, Nicholas A Wright, John A Bridgewater, Manuel Rodriguez-Justo, Chris P Barnes, Hemant M Kocher, Simon J Leedham, Andrea Sottoriva, Trevor A Graham.
      Aneuploidy is near-ubiquitous in cancer and contributes to tumor biology. However, the temporal evolutionary dynamics that select for aneuploidy remain uncharacterized. We performed longitudinal genomic analysis of 755 samples from 167 patients with colorectal-derived neoplasias from different stages through metastasis and treatment. Adenomas had few copy number alterations (CNA) and most were subclonal, whereas cancers had many clonal CNAs, suggesting that progression goes through a CNA bottleneck. Individual colorectal cancer glands from the same tumor had similar karyotypes, despite evidence of ongoing instability at the cell level. CNAs in metastatic lesions, after therapy, and in late recurrences were similar to the primary. Mathematical modeling indicated that these data are consistent with the action of negative selection on CNAs that "trap" cancer genomes on a fitness peak characterized by specific CNAs. Hence, progression to colorectal cancer requires traversing a rugged fitness landscape, whereas subsequent CNA evolution is constrained by negative selection.
    SIGNIFICANCE: We profiled 167 long-term responders longitudinally (755 samples), documenting long-term cancer evolution. We found that a genetic bottleneck is required for progression and is associated with dramatic increase in CNAs but decrease in clonal diversity. After initiation, copy number evolution is constrained by negative selection through metastasis and treatment.
    DOI:  https://doi.org/10.1158/2159-8290.CD-24-0813
  32. Sci Adv. 2026 Jan 23. 12(4): eadz9227
    Aberrant methylation limits antitumoral inflammation in lung adenocarcinoma by restricting RIPK3 expression.
    Deepti Agrawal, Katarina Cisarova, Sebastian Vosberg, Fabian Allmendinger, Enkhtsetseg Munkhbaatar, Nadia Dandachi, Francisco Jose Fernandez Hernandez, Marta Tonietto, Vanessa Jäger, Martina Anton, Eva C Keller, Moritz Jesinghaus, Anna-Lena Meinhardt, Verena Haefner, Tobias Stoeger, Katja Steiger, Nicholas McGranahan, Michael A Dengler, Adam Wahida, Philipp J Jost.
      Evasion of programmed cell death is a critical hallmark of cancer. However, the contribution of inflammatory forms of cell death in lung carcinogenesis and their effects on the composition of the tumor-immune microenvironment remain unclear. Our multi-omics analyses of samples from patients with primary lung adenocarcinoma revealed that necrosome signaling is repressed because of reduced expression of receptor-interacting protein kinase 3 (RIPK3). Distinct methylation signatures, both in the RIPK3 promoter and nonpromoter regions, correlated with lower transcription levels of RIPK3. This resulted in limited expression of inflammatory genes, advanced histologic features, reduced immune cell invasion, and decreased patient survival. Mechanistically, we confirmed the tumor-suppressive role of necrosome signaling through the genetic deletion of Ripk3 in two independent, clinically relevant mouse models of lung adenocarcinoma. Functionally, RIPK3 shaped a diverse immune environment by promoting the invasion of innate and adaptive immune cells in patient samples and experimental mice. Thus, RIPK3-mediated inflammatory signaling enhances a diverse immune microenvironment and hinders progression in lung adenocarcinoma.
    DOI:  https://doi.org/10.1126/sciadv.adz9227
  33. Cell Rep Med. 2026 Jan 20. pii: S2666-3791(25)00638-X. [Epub ahead of print]7(1): 102565
    CRISPR screens in the context of immune selection identify CHD1 and MAP3K7 as mediators of cancer immunotherapy resistance.
    Alex Watterson, Gabriele Picco, Vivien Veninga, Youhani Samarakoon, Chiara M Cattaneo, Sara F Vieira, Emre Karakoc, Shriram Bhosle, Thomas W Battaglia, Sarah Consonni, Timotheus Y F Halim, Emile E Voest, Mathew J Garnett, Matthew A Coelho.
      Cancer immunotherapy is only effective in a subset of patients, highlighting the need for effective biomarkers and combination therapies. Here, we systematically identify genetic determinants of cancer cell sensitivity to anti-tumor immunity by performing whole-genome CRISPR-Cas9 knockout screens in autologous tumoroid-T cell co-cultures, isogenic cancer cell models deficient in interferon signaling, and in the context of four cytokines. We discover that loss of CHD1 and MAP3K7 (encoding TAK1) potentiates the transcriptional response to IFN-γ, thereby creating an acquired vulnerability by sensitizing cancer cells to tumor-reactive T cells. Immune checkpoint blockade is more effective in a syngeneic mouse model of melanoma deficient in Chd1 and Map3k7 and is associated with elevated intra-tumoral CD8+ T cell numbers and activation. CHD1 and MAP3K7 are recurrently mutated in cancer, and reduced expression in tumors correlates with response to immune checkpoint inhibitors in patients, nominating these genes as potential biomarkers of immunotherapy response.
    Keywords:  CHD1; CRISPR-Cas9; IFN-γ; MAP3K7; T cells; TAK1; cancer immunotherapy; co-culture screen; immmune checkpoint blockade; resistance
    DOI:  https://doi.org/10.1016/j.xcrm.2025.102565
  34. Trends Biochem Sci. 2026 Jan 16. pii: S0968-0004(25)00306-8. [Epub ahead of print]
    A metabolic link between DNA synthesis and chromatin assembly.
    Laura Quintero-Pantoja, Gonzalo Millán-Zambrano.
      Metabolic enzymes are emerging as key regulators of nuclear processes. A recent study by Srivastava et al. shows that the nucleotide biosynthetic enzyme phosphoribosyl pyrophosphate synthetase 1 participates in early histone maturation, highlighting a direct molecular link between metabolic state and chromatin assembly.
    Keywords:  H3–H4 chromatin assembly; histone maturation; nucleotide metabolism; phosphoribosyl pyrophosphate synthetase 1
    DOI:  https://doi.org/10.1016/j.tibs.2025.12.014
  35. Nat Genet. 2026 Jan 22.
    Genomic evolution of pancreatic cancer at single-cell resolution.
    Haochen Zhang, Palash Sashittal, Elias-Ramzey Karnoub, Akhil Jakatdar, Shigeaki Umeda, Jungeui Hong, Anne Marie Noronha, Agustin Cardenas, Amanda Erakky, Caitlin A McIntyre, Akimasa Hayashi, Nicolas Lecomte, Marc Hilmi, Wungki Park, Nan Pang, Eileen M O'Reilly, Alice C Wei, Benjamin J Raphael, Christine A Iacobuzio-Donahue.
      Most evolutionary studies on pancreatic cancer rely on bulk sequencing, yet clonal evolution happens at the single-cell level. We used single-nucleus DNA sequencing to study 137,491 single nuclei from 24 pancreatic neoplasms reflecting various clinical scenarios. We found higher frequencies of somatic alterations to driver genes that bulk studies indicate; many manifest as copy number alterations and account for the majority of spatial heterogeneity. In pancreatic cancers with canonical KRAS oncogenic mutations, we found likely varied dependence on the genotype that may signify differential response to KRAS inhibition. In pancreatic cancers with germline heterozygous BRCA2 mutations, we discovered varied mechanisms and timing of inactivation of the wild-type allele that sculpted differential evolutionary trajectories. Inactivation of tumor-intrinsic response to transforming growth factor-β happens through various mechanisms, takes place after oncogenesis and coincides with invasion and metastasis, reflecting increasing selective pressure for the phenotype later in pancreatic ductal adenocarcinoma development.
    DOI:  https://doi.org/10.1038/s41588-025-02468-9
  36. JID Innov. 2026 Mar;6(2): 100441
    Spatially controlled induction and regression of basal cell carcinoma, visualized by serial imaging in young and old mice.
    Elisabeth A Pedersen, Marina Grachtchouk, Paul W Harms, Allison K C Furgal, Dawn Wilbert, Allesandra Hoover, Daryna V Hodgson, Katelyn Fiehler, Anissa Alam, Nihal Lingam, Sunny Y Wong, Monique E Verhaegen, Andrzej A Dlugosz.
      Basal cell carcinoma (BCC) is the most common skin malignancy, and the risk of developing BCC increases with age. BCC results from dysregulated Hedgehog signaling leading to activation of GLI transcription factors. In this study, we examined the impact of aging on BCC in cohorts of young (n = 37) versus aged (n = 97) mice using a transgenic mouse model in which GLI2A (GLI2 activator) was induced in mice at either the age of 7 weeks or 22-24 months, and BCC tumor development was monitored by weekly imaging. Young mice developed tumors slightly sooner and in greater numbers than aged mice but demonstrated similar growth rates once tumors appeared. However, BCC-associated increases in blood vessel diameter, tortuosity, and ulceration were impacted by age. BCCs in both young and aged mice underwent similarly rapid regression after GLI2A transgene inactivation. Taken together, our findings reveal that aging affects tumor-associated vasculature but not BCC formation or regression in our model. These results are in keeping with the notion that a major contributor to the increased incidence of BCCs in elderly patients is the accumulation of oncogenic driver mutations over time rather than intrinsic changes in aged skin that promote BCC tumorigenesis.
    Keywords:  Aging; Basal cell carcinoma; Imaging; Mouse models
    DOI:  https://doi.org/10.1016/j.xjidi.2025.100441
  37. Nat Commun. 2026 Jan 21. 17(1): 770
    Spatiotemporal regulation of energetic charge dictates T cell function.
    Aleksandra S Chikina, Béatrice Corre, Fabrice Lemaître, Philippe Bousso.
      Immune cell functions are dictated by their differentiation state and regulated by transcriptional and epigenetic changes. Immune cell differentiation also controls the preferential metabolic pathways used for energy production. However, whether the energy charge of individual immune cells itself varies across time and space and regulates cell function remains to be fully understood. Here, we show that T cells harbor distinct energetic resources and function in different anatomical locations and times of the day. To monitor ATP: ADP ratio, an indicator of cellular energetic resources, we rely on SPICE-Met, a method that dissects energy metabolism in complex cell populations in vivo. We find that cells with the highest glycolytic capacity, including effector T cells and NK cells, exhibit the highest ATP: ADP ratio. Importantly, effector T cells but not naïve T cells display higher energetic charge when present in the blood compared to lymph nodes due to differential glucose availability. Energetic resources are also regulated in a circadian manner, being highest at the early rest phase. Importantly, differences in energetic charge are directly translated at the level of T cell function, impacting IFN-γ production. Thus, modulation of energetic charge and nutrient availability dictates immune cell function across time and space.
    DOI:  https://doi.org/10.1038/s41467-026-68559-1
  38. Nat Metab. 2026 Jan 21.
    IL-21 mediates crosstalk between T cells and NK cells during the remission of type 1 diabetes.
    Kang Lei, Xinyu Li, Ting Zhong, Rong Tang, Qiaolin Deng, Paul E Love, Zhiguang Zhou, Bin Zhao, Xia Li.
      The innate immune system is increasingly recognized as a contributor to the development of type 1 diabetes (T1D), but the role of natural killer (NK) cells remains largely unclear. Here, we identify an expanded subset of transcriptionally active CD226+CD56dimCD16+ NK cells at the onset of T1D that contracts in remission. Using single-cell RNA sequencing integrated with cross-sectional and longitudinal analyses in patients with T1D, we show that CD226+ NK cell frequency correlates with disease progression. CD226+ NK cells exhibit enhanced cytotoxicity, inflammation and glucose metabolism. Mechanistically, CD161+CD4+ T cells promote pathogenic NK cell generation through interleukin-21 (IL-21) and mTOR signalling. Inhibition of this pathway by CD226 blockade, IL-21 receptor fusion protein, IL-21 knockout or mTOR inhibition attenuates NK cell activation, reduces pancreatic infiltration and delays diabetes onset in female mice. Our data reveal a mechanistic link, bridging adaptive and innate immunity, in the progression and remission of T1D that could potentially be exploited in T1D immunotherapy.
    DOI:  https://doi.org/10.1038/s42255-025-01439-y
  39. Clin Nutr. 2026 Jan 09. pii: S0261-5614(26)00002-6. [Epub ahead of print]57 106575
    The 2025 Sir David Cuthbertson Lecture: Energy metabolism: Beyond calories, feeding the mitochondria.
    Eric Fontaine.
      In this article, I explore how energy metabolism depends on proper mitochondrial function. Adenosine triphosphate (ATP), the main source of energy for cells, is mainly produced in the mitochondria as a result of the fusion of hydrogen produced by the breakdown of nutrients with oxygen. This reaction allows protons to be pumped across the inner mitochondrial membrane, creating a gradient that powers ATP synthesis. However, ATP production is not perfectly efficient. Some oxygen is consumed without generating ATP due to proton leaks or other processes that utilize the gradient. Diet, hormones, and cellular signals can alter mitochondrial efficiency: for example, hyperthyroidism and polyunsaturated fatty acid deficiency cause uncoupling, while hypothyroidism and nitric oxide increase coupling but reduce maximum ATP production. I also point out that the use of ATP depends on its thermodynamic value, which is reflected in the Adenosine triphosphate/Adenosine diphosphate ratio ([ATP]/[ADP] ratio). A decrease in this ratio can selectively reduce certain ATP-consuming processes, as shown in studies on metformin and imeglimin. In cases of stress or nutritional deficiency, cells can consume ATP without performing useful work, leading to inefficiency or even cell death when the [ATP]/[ADP] ratio collapses. Knowing that these concepts are quite complex, I have simplified them to make clear that mitochondria are more than just passive "powerhouses of cells".
    Keywords:  Efficiency; Energy metabolism; Flux–force relationship; Kinetics; Mitochondria; Thermodynamics
    DOI:  https://doi.org/10.1016/j.clnu.2026.106575
  40. Am J Pathol. 2026 Feb;pii: S0002-9440(25)00412-2. [Epub ahead of print]196(2): 515-531
    Stimulator of Interferon Genes Is a Fine-Tuner, but Not a Prime Mover, of Kidney Inflammation.
    Madiha Zahra Syeda, Emily S H Yeung, Lisa Y Q Hong, Suzanne L Advani, Youan Liu, Laurette Geldenhuys, Ferhan S Siddiqi, Veera Ganesh Yerra, Sri Nagarjun Batchu, Andrew Advani.
      Recent years have seen substantial scientific excitement in the role that the double-stranded DNA sensor and mediator of inflammation, stimulator of interferon genes (STING), plays in kidney disease. However, the STING pathway is not the sole regulator of inflammation, and STING has roles other than in inflammation. Here, elevated STING levels were observed in both human and mouse kidney disease, and the effects of STING deletion from kidney tubule cells, myeloid cells, and globally in experimental kidney disease were examined. Inflammatory gene up-regulation in tubule cells, induced by double-stranded DNA, was attenuated (but not negated) by STING knockout. Either myeloid or global knockout of STING marginally diminished fibroinflammatory gene up-regulation in mice with kidney injury caused by unilateral ureteral obstruction, whereas tubule cell knockout of STING unexpectedly augmented inflammatory gene up-regulation. Global knockout of STING similarly worsened diabetic kidney disease, likely due to heightened hyperglycemia. Antagonism of STING attenuated autophagy induction in human tubule cells, but not in human glomerular endothelial cells or podocytes. These findings serve as a counterweight to the enthusiasm that has recently emerged as to the roles of STING-mediated signaling in kidney disease. The actions of STING extend beyond its role in inflammation, and they are cell type dependent. STING may be a fine-tuner, but it is unlikely to be a prime mover, of inflammation in kidney disease.
    DOI:  https://doi.org/10.1016/j.ajpath.2025.10.013
  41. Nat Metab. 2026 Jan 20.
    Distinct sympathetic projections to brown fat regulate thermogenesis and glucose tolerance.
    Daniele Neri, Seoeun Lee, Alexis M Fohn, Xinhong Chen, Dominique Bozec, Alexandre J Lafond, Natalie R Lopatinsky, Lucas Castro E Souza, Gawri Mohanan Nair, Angela M Ramos-Lobo, Markus Heine, Anna Worthmann, Joerg Heeren, Vidhu V Thaker, Viviana Gradinaru, Lori M Zeltser.
      Brown adipose tissue (BAT) contributes to thermoregulation and glucose metabolism, but how these functions are coordinated remains unclear. While thermogenesis in the activated BAT typically coincides with increased blood flow and glucose uptake1-5, several pathophysiological and nutritional states dissociate these processes6,7, suggesting they are governed by distinct sympathetic circuits. Here we identify subpopulations of sympathetic neurons in the stellate ganglion that mediate distinct functions of intrascapular BAT (iBAT) in mice. Two main types of sympathetic neurons project to iBAT: those that innervate the organ parenchyma and those that innervate the large blood vessels feeding the depot8-12. Here we develop a toolkit to parse the functions of these neuronal subclasses through targeted chemogenetic activation of projections to iBAT, while sparing other organs, and single-cell transcriptomics coupled to retrograde tracing from iBAT to the stellate ganglion. We find that stimulation of the parenchymal projections increases blood flow and thermogenesis in iBAT, without affecting circulating glucose levels. Conversely, stimulation of the vascular projections improves glucose tolerance but does not alter blood flow or thermogenesis in iBAT. These data provide a mechanistic explanation for the dissociation between the thermogenic and glycaemic effects of BAT activation13-16.
    DOI:  https://doi.org/10.1038/s42255-025-01429-0
  42. Nature. 2026 Jan 21.
    Oxygen-free metabolism in the bird inner retina supported by the pecten.
    Christian Damsgaard, Mia Viuf Skøtt, Catherine J A Williams, Hans Malte, Camilla Kruse Kidmose, Morten Busk, Karin Dedek, Andreas H Konradsen, Anne Sofie Stengel Rasmussen, Jesper Skovhus Thomsen, Anna V G T Mikkelsen, Katrine S Johannsen, Mikkel Vendelbo, Niels Peter Revsbech, Coen P H Elemans, Henrik Mouritsen, Joanna Kalucka, Lin Lin, Nina Kerting Iversen, Tobias Wang, Henrik Lauridsen, Jens Randel Nyengaard.
      Neural tissues are exceptionally sensitive to oxygen deprivation and rely on a dense network of blood vessels to support their extraordinarily high metabolic demands for oxygen, nutrients and clearance of waste products1-4. In birds, one of the metabolically most demanding neural tissue-the retina-lacks internal blood vessels5,6. This raises the question of how such a metabolically demanding neural tissue can function without blood perfusion. Here we show that, while the photoreceptor outer segments in the outer retina have access to oxygen, the inner bird retina operates under chronic anoxia, supported by anaerobic glycolysis in the retinal neurons. We provide evidence that the pecten oculi-a uniquely vascularized structure in the vitreous humour of birds, the function of which has been debated for centuries5-9-supplies the anoxic inner retina with glucose and removes lactic acid. We suggest that the pecten's metabolic support of the bird retina's anoxia tolerance enabled first the evolution of a thick cell-dense, avascular retina, which secondarily served as an exaptation enabling retinal function during high-altitude migrations.
    DOI:  https://doi.org/10.1038/s41586-025-09978-w
  43. Biochem Pharmacol. 2026 Jan 18. pii: S0006-2952(26)00051-1. [Epub ahead of print] 117720
    Macrophage migration inhibitory factor superfamily in tumor metabolism: mechanistic insights and therapeutic potential.
    Wenli Xie, Yanlei Dong, Jiao Lv, Xiangyu Wang.
      Macrophage migration inhibitory factor (MIF) is a versatile cytokine that links inflammation to tumor metabolism. It signals through CD74, along with co-receptors C-X-C chemokine receptor 2, 4, and 7 (CXCR2/CXCR4/CXCR7), activating the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) and extracellular signal-regulated kinase (ERK) pathways. MIF also engages the mechanistic target of rapamycin complex 1 (mTORC1)/activating transcription factor 4 (ATF4) module to reprogram metabolic processes. This review explains how MIF promotes glucose uptake and aerobic glycolysis (the Warburg effect) and coordinates lipid regulators-sterol regulatory element-binding proteins (SREBPs) and peroxisome proliferator-activated receptors (PPARs)-to enhance lipid uptake, de novo lipogenesis, acyl-chain remodeling, β-oxidation flexibility, and cholesterol/membrane homeostasis. It also reshapes amino acid transport, glutamine utilization, redox balance, and sensitivity to ferroptosis. The focus is on receptor-specific entry points, module-level outcomes, and how the tumor microenvironment affects nutrient competition and immune suppression. To avoid over-interpretation, evidence is graded by strength: [1] direct target engagement with pathway pharmacodynamics; [2] pathway-level signals alone; and [3] scaffold-level plausibility. Validation uses a standard set of assays, including orthogonal biophysical methods, receptor-proximal pharmacodynamic readouts, and isotope-tracing flux measurements. The review critically assesses current small-molecule classes targeting the catalytic pocket or trimer/interface to identify design principles for next-generation, receptor-focused modulators suitable for combination therapy. Finally, it proposes an imaging- and flux-based translational approach to select patients, confirm on-target action, and rationally pair MIF-axis blockade with metabolic or immunotherapeutic strategies-aiming to transform correlative data into mechanism-based clinical trials.
    Keywords:  Amino acid transport; CD74; Lipid metabolism; Macrophage migration inhibitory factor; Tumor metabolism
    DOI:  https://doi.org/10.1016/j.bcp.2026.117720
  44. Nat Commun. 2026 Jan 19.
    Longitudinal analysis of body weight reveals homeostatic and adaptive traits linked to lifespan in diversity outbred mice.
    G V Prateek, Zhenghao Chen, Kevin Wright, Andrea Di Francesco, Vladimir Jojic, Gary A Churchill, Anil Raj.
      Dense temporal measurements of physiological health, using simple and consistent assays, are essential to characterize biological processes associated with aging and evaluate the effectiveness of interventions on these processes. We measured body weight in 960 genetically diverse female mice, every 7-10 days over the full course of their lifespan. We used a state space model to characterize the trajectories of body weight throughout life and derived novel traits capturing the dynamics of body weight, 10 of which were both heritable and associated with lifespan. Genetic mapping of these body weight-derived traits identified 5 genomic loci, none of which were previously mapped to body weight. We observed that the ability to maintain stable body weight, despite fluctuations in energy intake and expenditure, was positively associated with lifespan in an age-dependent manner and mapped to a genomic locus linked to energy homeostasis. Our results highlight how dense longitudinal measurements of physiological phenotypes offer new insights into the biology of aging.
    DOI:  https://doi.org/10.1038/s41467-026-68392-6
  45. EMBO J. 2026 Jan 22.
    The lysosomal LAMTOR-Rag complex functions as a checkpoint for antiviral interferon production.
    Zeming Feng, Lulu Wang, Shujun Chen, Sihan Cao, Miao Lei, Xiuzhen Yang, Kaixiong Ma, Shi Yu, Huina Hu, Kaixuan Zheng, Xin Xu, Qi Zheng, Shaobo Wang, Wenxiang Hu, Chun-Yan Lim.
      Lysosomes are emerging as important signaling hubs for antiviral defense, yet how they enable type I interferon (IFN-β) production is unclear. Here, we identify an evolutionarily repurposed lysosomal pathway, centered on the LAMTOR-Rag GTPase complex, that governs IFN-β production through dual transcriptional and post-transcriptional regulation. Genetic ablation of LAMTOR or Rag GTPases in macrophages abolishes IFN-β responses despite intact pattern recognition receptor (PRR) signaling, uncovering a lysosome-specific checkpoint essential for antiviral immunity. Mechanistically, Rag GTPase activity controls IRF expression to prime IFN transcription, while upon PRR stimulation, the tumor suppressor FLCN recruits p38 MAPK to lysosomes, where Rag-dependent p38 phosphorylation stabilizes Ifnb1 mRNA. Nutrient availability dynamically modulates Rag nucleotide states and thereby its activation, linking IFN production to metabolic capacity. Notably, this checkpoint operates independently of mTORC1, illustrating how an ancient nutrient-sensing module has been co-opted for immune regulation. Disruption of the LAMTOR-Rag-FLCN-p38 axis impairs IFN induction in vitro and antiviral responses in vivo, underscoring its physiological significance. Our findings support the role of the lysosome as a central signaling hub integrating metabolic and immune cues, suggesting future directions for potential therapeutic strategies against viral infections.
    Keywords:  Innate Immunity; LAMTOR/Ragulator; Lysosomes; Type I Interferon; p38 MAPK
    DOI:  https://doi.org/10.1038/s44318-026-00695-2
  46. Nat Commun. 2026 Jan 22.
    Single-cell atlas of human lung aging identifies cell type dyssynchrony and increased transcriptional entropy.
    Ruben De Man, John E McDonough, Taylor S Adams, Fadi Nikola, Reina Rangel, Sabina Anderson, Edward P Manning, Juan Cala Garcia, Benjamin Moss, Alan Waich, Fernando Poli, Rafael Cardenas, Cristian Coarfa, Qi Song, Ziv Bar-Joseph, Bart M Vanaudenaerde, Wim A Wuyts, Laura Niklason, Micha Sam B Raredon, Xiting Yan, Ivan O Rosas, Naftali Kaminski.
      Age is a major risk factor for lung disease. We characterized the changing cellular, transcriptional, and genomic landscape of human lung aging using single-cell RNA sequencing. We find that lung aging is cell-type dyssynchronous, with alveolar epithelial and endothelial cells exhibiting the greatest transcriptional changes. Among alveolar epithelial cells, aging is associated with a decreased relative proportion of surfactant-expressing SPChigh AT2 cells. Among alveolar capillary cells, we observed loss of differentiation and capillary function. Analysis of somatic mutations called from single-cell data revealed an increase with aging, with alveolar epithelial and endothelial cell types exhibiting greater mutation burdens. Transcriptional entropy was increased with aging and was an independent predictor of age. Notably, cells expressing commonly accepted senescence signatures did not increase with age. Our results reveal cell type dyssynchrony in human lung aging with age-related changes concentrated in alveolar epithelial and endothelial cells.
    DOI:  https://doi.org/10.1038/s41467-026-68810-9
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