N Nature Metabolism · Dec 05, 2025 Pathway coessentiality mapping reveals complex II is required for de novo purine biosynthesis in acute myeloid leukaemia Understanding how cellular pathways interact is crucial for treating complex diseases like cancer. Individual gene–gene interaction studies have provided valuable insights, but may miss pathways working together. Here we develop a multi-gene approach to pathway mapping which reveals that acute myeloid leukaemia (AML) depends on an unexpected link between complex II and purine metabolism. Through stable-isotope metabolomic tracing, we show that complex II directly supports de novo purine biosynthesis and that exogenous purines rescue AML cells from complex II inhibition. The mechanism involves a metabolic circuit where glutamine provides nitrogen to build the purine ring, producing glutamate that complex II metabolizes to sustain purine synthesis. This connection translates into a metabolic vulnerability whereby increasing intracellular glutamate levels suppresses purine production and sensitizes AML cells to complex II inhibition. In a syngeneic AML mouse model, targeting complex II leads to rapid disease regression and extends survival. In individuals with AML, higher complex II gene expression correlates with resistance to BCL-2 inhibition and worse survival. These findings establish complex II as a central regulator of de novo purine biosynthesis and a promising therapeutic target in AML. Acute myeloid leukaemia Cancer metabolism Metabolism Metabolomics biology mouse experiments
N Nature Metabolism · Dec 03, 2025 Age-related decline of chaperone-mediated autophagy in skeletal muscle leads to progressive myopathy Chaperone-mediated autophagy (CMA) contributes to proteostasis maintenance by selectively degrading a subset of proteins in lysosomes. CMA declines with age in most tissues, including skeletal muscle. However, the role of CMA in skeletal muscle and the consequences of its decline remain poorly understood. Here we demonstrate that CMA regulates skeletal muscle function. We show that CMA is upregulated in skeletal muscle in response to starvation, exercise and tissue repair, but declines in ageing and obesity. Using a muscle-specific CMA-deficient mouse model, we show that CMA loss leads to progressive myopathy, including reduced muscle force and degenerative myofibre features. Comparative proteomic analyses reveal CMA-dependent changes in the mitochondrial proteome and identify the sarcoplasmic–endoplasmic reticulum Ca2+-ATPase (SERCA) as a CMA substrate. Impaired SERCA turnover in CMA-deficient skeletal muscle is associated with defective calcium (Ca2+) storage and dysregulated Ca2+dynamics. We confirm that CMA is also downregulated with age in human skeletal muscle. Remarkably, genetic upregulation of CMA activity in old mice partially ameliorates skeletal muscle ageing phenotypes. Together, our work highlights the contribution of CMA to skeletal muscle homoeostasis and myofibre integrity. Ageing Chaperone-mediated autophagy Metabolism Skeletal muscle biology mouse experiments
N Nature Metabolism · Dec 03, 2025 Chaperone-mediated autophagy sustains muscle stem cell regenerative functions but declines with age Proteostasis supports stemness, and its loss correlates with the functional decline of diverse stem cell types. Chaperone-mediated autophagy (CMA) is a selective autophagy pathway implicated in proteostasis, but whether it plays a role in muscle stem cell (MuSC) function is unclear. Here we show that CMA is necessary for MuSC regenerative capacity throughout life. Genetic loss of CMA in young MuSCs, or failure of CMA in aged MuSCs, causes proliferative impairment resulting in defective skeletal muscle regeneration. Using comparative proteomics to identify CMA substrates, we find that actin cytoskeleton organization and glycolytic metabolism are key processes altered in aged murine and human MuSCs. CMA reactivation and glycolysis enhancement restore the proliferative capacity of aged mouse and human MuSCs, and improve their regenerative ability. Overall, our results show that CMA is a decisive stem cell-fate regulator, with implications in fostering muscle regeneration in old age. Chaperone-mediated autophagy Muscle stem cells biology mouse experiments
N Nature Metabolism · Dec 01, 2025 Fat sensory cues in early life program central response to food and obesity Maternal obesity predisposes offspring to metabolic diseases. Here, we show that non-nutritive sensory components of a high-fat diet (HFD), beyond its hypercaloric, obesogenic effects, are sufficient to alter metabolic health in the offspring. To dissociate the caloric and sensory components of HFD, we fed dams a bacon-flavoured diet, isonutritional to a normal chow diet but enriched with fat-related odours. Offspring exposed to these fat-related odours during development display metabolic inflexibility and increased adiposity when fed HFD in adulthood independently of maternal metabolic health. Developmental exposure to fat-related odours shifts mesolimbic dopaminergic circuits and Agouti-related peptide (AgRP) hunger neurons’ responses to phenocopy those of obese mice, including a desensitization of AgRP neurons to dietary fat. While neither neonatal optogenetic activation of sensory circuits nor passive exposure to fat-related odours is sufficient to alter metabolic responses to HFD, coupling optogenetic stimulation of sensory circuits with caloric intake exacerbates obesity. Collectively, we report that fat-related sensory cues during development act as signals that can prime central responses to food cues and whole-body metabolism regulation. Feeding behaviour Obesity biology mouse experiments
N Nature Metabolism · Nov 20, 2025 Hepatocyte mitochondrial NAD+content is limiting for liver regeneration Nicotinamide adenine dinucleotide (NAD+) precursor supplementation shows metabolic and functional benefits in rodent models of disease and is being explored as potential therapeutic strategy in humans. However, the wide range of processes that involve NAD+in every cell and subcellular compartment make it difficult to narrow down the mechanisms of action. Here we show that the rate of liver regeneration is closely associated with the concentration of NAD+in hepatocyte mitochondria. We find that the mitochondrial NAD+concentration in hepatocytes of male mice is determined by the expression of the transporter SLC25A51 (MCART1). The heterozygous loss of SLC25A51 modestly decreases mitochondrial NAD+content in multiple tissues and impairs liver regeneration, whereas the hepatocyte-specific overexpression of SLC25A51 is sufficient to enhance liver regeneration comparably to the effect of systemic NAD+precursor supplements. This benefit is observed even though NAD+levels are increased only in mitochondria. Thus, the hepatocyte mitochondrial NAD+pool is a key determinant of the rate of liver regeneration. Energy metabolism Homeostasis Metabolomics
N Nature Metabolism · Nov 14, 2025 Glycerol-3-phosphate activates ChREBP, FGF21 transcription and lipogenesis in citrin deficiency Citrin deficiency (CD) is caused by the inactivation of SLC25A13, a mitochondrial membrane protein required to move electrons from cytosolic NADH to the mitochondrial matrix in hepatocytes. People with CD do not like sweets. Here we show that SLC25A13 loss causes the accumulation of glycerol-3-phosphate (G3P), which activates the carbohydrate response element-binding protein (ChREBP) to transcribe FGF21, which acts in the brain to restrain intake of sweets and alcohol and to transcribe key genes driving lipogenesis. Mouse and human data suggest that G3P–ChREBP is a mechanistic component of the Randle Cycle that contributes to metabolic-dysfunction-associated steatotic liver disease and forms part of a system that communicates metabolic states from the liver to the brain in a manner that alters food and alcohol choices. The data provide a framework for understanding FGF21 induction in varied conditions, suggest ways to develop FGF21-inducing drugs and suggest potential drug candidates for lean metabolic-dysfunction-associated steatotic liver disease and support of urea cycle function in CD. Gene regulation Liver Metabolic diseases Metabolism Transcriptional regulatory elements
N Nature Metabolism · Nov 13, 2025 Uridine-sensitized screening identifies demethoxy-coenzyme Q and NUDT5 as regulators of nucleotide synthesis Rapidly proliferating cells require large amounts of nucleotides, making nucleotide metabolism a widely exploited therapeutic target against cancer, autoinflammatory disorders and viral infections. However, regulation of nucleotide metabolism remains incompletely understood. Here, we reveal regulators of de novo pyrimidine synthesis. Using uridine-sensitized CRISPR-Cas9 screening, we show that coenzyme Q (CoQ) is dispensable for pyrimidine synthesis, in the presence of the demethoxy-CoQ intermediate as alternative electron acceptor. We further report that the ADP-ribose pyrophosphatase NUDT5 directly binds PPAT, the rate-limiting enzyme in purine synthesis, which inhibits its activity and preserves the phosphoribosyl pyrophosphate (PRPP) pool. In the absence of NUDT5, hyperactive purine synthesis exhausts the PRPP pool at the expense of pyrimidine synthesis, which promotes resistance to purine and pyrimidine nucleobase analogues. Of note, the interaction between NUDT5 and PPAT is disrupted by PRPP, highlighting an intricate allosteric regulation. Overall, our findings reveal a fundamental mechanism of nucleotide balance and position NUDT5 as a regulator of nucleobase analogue metabolism. Metabolism Metabolomics Multienzyme complexes Nucleic acids
N Nature Metabolism · Nov 12, 2025 Impaired cAMP–PKA–CREB1 signalling drives mitochondrial dysfunction in skeletal muscle during cancer cachexia Skeletal muscle wasting is a defining feature of cancer cachexia, a multifactorial syndrome that drastically compromises patient quality of life and treatment outcomes. Mitochondrial dysfunction is a major contributor to skeletal muscle wasting in cancer cachexia, yet the upstream molecular drivers remain elusive. Here we show that cancer impairs the activity of cAMP-dependent protein kinase A (PKA) and of its transcriptional effector CREB1 in skeletal muscle, ultimately contributing to the downregulation of a core transcriptional network that supports mitochondrial integrity and function. The restoration of cAMP–PKA–CREB1 signalling through pharmacological inhibition of the cAMP-hydrolysing phosphodiesterase 4 (PDE4) rescues the expression of mitochondrial-related genes, improves mitochondrial function and mitigates skeletal muscle wasting in male mice. Altogether, our data identify tumour-induced suppression of the cAMP–PKA–CREB1 axis as a central mechanism contributing to mitochondrial dysfunction in skeletal muscle during cancer cachexia. Furthermore, these findings highlight PDE4, particularly the PDE4D isoform, as a potential therapeutic target to preserve muscle mitochondrial function and counteract muscle wasting in cancer cachexia. Cancer Cell signalling Metabolism Mitochondria Skeletal muscle
N Nature Metabolism · Nov 10, 2025 Identification of a common ketohexokinase-dependent link driving alcohol intake and alcohol-associated liver disease in mice Alcohol and sugar share reinforcing properties and both contribute to liver disease progression, ultimately leading to cirrhosis. Emerging evidence suggests that ethanol activates the aldose reductase pathway, resulting in endogenous fructose production. Here we investigated whether alcohol preference and alcohol-associated liver disease (ALD) are mediated through fructose metabolism by ketohexokinase (KHK)-A/C. Using global, conditional and tissue-specific KHK-A/C knockout mice, we assessed ethanol intake, reinforcement behaviours and liver injury. Ethanol consumption increased portal vein osmolality and activated the polyol pathway in the liver and intestine, leading to fructose production metabolized by KHK-A/C. Mice lacking KHK-A/C showed reduced ethanol preference across multiple paradigms, including two-bottle choice, conditioned place preference and operant self-administration, alongside decreased ∆FosB expression in the nucleus accumbens. Both genetic deletion and pharmacologic inhibition of KHK-A/C suppressed ethanol intake. Hepatocyte-specific KHK-A/C knockout mice displayed partially reduced alcohol consumption, potentially linked to altered aldehyde dehydrogenase expression, while intestinal KHK-A/C deletion restored glucagon-like peptide-1 levels—a hormone known to suppress alcohol intake. Under ethanol pair-matched conditions, global and liver-specific KHK-A/C knockout mice were protected from ALD, with marked reductions in hepatic steatosis, inflammation and fibrosis. These findings identify ethanol-induced fructose metabolism as a key driver of excessive alcohol consumption and ALD pathogenesis. Given that ALD and metabolic dysfunction-associated steatotic liver disease share fructose-dependent mechanisms, targeting fructose metabolism may offer a novel therapeutic approach for treating alcohol use disorder and related liver injury. Metabolic diseases Metabolic disorders Metabolism
N Nature Metabolism · Nov 06, 2025 Blood methylome signatures in children exposed to maternal type 1 diabetes are linked to protection against islet autoimmunity Exposure to maternal type 1 diabetes (T1D) during pregnancy provides relative protection against T1D in the offspring. This protective effect may be driven by epigenetic mechanisms. Here we conducted an epigenome-wide blood analysis on 790 young children with and 962 children without a T1D-affected mother, and identified differential DNA methylation (q< 0.05) at multiple loci and regions. These included the Homeobox A gene cluster and 15 T1D susceptibility genes. The differential methylation was found in transcriptionally relevant regions associated with immune function, including sites previously linked to T1D-related methylation loci and protein biomarkers. Propensity scores for methylation at T1D susceptibility loci could predict the development of islet autoimmunity in offspring born to mothers without T1D. Together, these findings highlight pathways through which maternal T1D may confer protection against islet autoimmunity in offspring and suggest that environmental factors can influence T1D risk through epigenetic modifications of T1D susceptibility loci. Epigenomics Metabolism Type 1 diabetes
N Nature Metabolism · Nov 04, 2025 Mitochondrial complex III-derived ROS amplify immunometabolic changes in astrocytes and promote dementia pathology Neurodegenerative disorders alter mitochondrial functions, including the production of reactive oxygen species (ROS). Mitochondrial complex III (CIII) generates ROS implicated in redox signalling, but its triggers, temporal dynamics, targets and disease relevance are not clear. Here, using site-selective suppressors and genetic manipulations together with live mitochondrial ROS imaging and multiomic profiling, we show that CIII is a dominant source of ROS production in astrocytes exposed to neuropathology-related stimuli. Astrocytic CIII ROS production is dependent on nuclear factor-κB and the mitochondrial sodium-calcium exchanger (NCLX) and causes oxidation of select cysteines within immune- and metabolism-associated proteins linked to neurological disease. CIII ROS amplify metabolomic and pathology-associated transcriptional changes in astrocytes, with STAT3 activity as a major mediator, and facilitate neuronal toxicity. Therapeutic suppression of CIII ROS in mice decreases dementia-linked tauopathy and neuroimmune cascades and extends lifespan. Our findings establish CIII ROS as an important immunometabolic signal transducer and tractable therapeutic target in neurodegenerative disease. Astrocyte Dementia Mechanisms of disease Metabolism Mitochondria
N Nature Metabolism · Oct 22, 2025 Oligodendrocyte precursor cell-specific blocking of low-glucose-induced activation of AMPK ensures myelination and remyelination It has been shown that in most cells, low glucose leads to activation of AMP-activated protein kinase (AMPK) via the lysosomal glucose-sensing pathway, where glycolytic aldolase acts as the glucose sensor. Here, we show that ALDOC (aldolase C), the predominant isozyme of aldolase in mouse and rat oligodendrocyte precursor cells (OPCs), is acetylated at lysine 14, making the lysosomal glucose-sensing AMPK pathway unable to operate. We find that the blockage of AMPK activation is required for the proper proliferation and differentiation of OPCs into mature oligodendrocytes for myelination during development and for remyelination in areas of demyelination where the local glucose levels are low. Therefore, the acetylation of aldolase acts as a checkpoint for AMPK activation in response to low glucose to ensure the proliferation and differentiation of OPCs for myelination, and remyelination of demyelinated neurons. Acetylation Metabolism Nervous system Neurogenesis Nutrient signalling
N Nature Metabolism · Oct 21, 2025 Microbial metabolite indole-3-propionic acid drives mitochondrial respiration in CD4+T cells to confer protection against intestinal inflammation The gut microbiota and its metabolites critically regulate immune cell phenotype, function and energy metabolism. We screened a collection of gut microbiota-related metabolites to identify modulators of mitochondrial metabolism in T cells. Here we show that indole-3-propionic acid (IPA) stimulates mitochondrial respiration of CD4+T cells by increasing fatty acid oxidation (FAO) and amino acid oxidation (AAO), while inhibiting glycolytic capacity. IPA also impacts CD4+T cell behaviour by inhibiting their differentiation to type 1 and type 17 helper T cell phenotypes. Mechanistically, the metabolic and immune effects of IPA are mediated by peroxisome proliferator-activated receptor-β/δ. The administration of IPA rescues mitochondria respiration in mice with gut bacteria depletion or colitis by enhancing FAO and AAO in colonic CD4+T cells. Adoptive transfer experiments show that IPA acts on CD4+T cells to exert its protective effect against inflammation. Collectively, our study reveals that the anti-inflammatory effects of IPA are mediated by metabolic reprogramming of CD4+T cells toward the enhancement of mitochondrial respiration. Inflammatory bowel disease Metabolism Microbiome Mitochondria Mucosal immunology
N Nature Metabolism · Oct 20, 2025 Tumour-associated macrophages serve as an acetate reservoir to drive hepatocellular carcinoma metastasis Increased acetyl-coenzyme A (acetyl-CoA) generation facilitates cancer metastasis and represents a critical metabolic characteristic of metastatic cancers. To maintain high acetyl-CoA levels, cancer cells often enhance the uptake of acetate for acetyl-CoA biosynthesis. However, the microenvironmental source of acetate remains largely unknown. Here we demonstrate that acetate is secreted by tumour-associated macrophages (TAMs) and taken up by hepatocellular carcinoma (HCC) cells to support acetate accumulation. Mechanistically, HCC cell-derived lactate activates the lipid peroxidation–aldehyde dehydrogenase 2 (ALDH2) pathway in TAMs, which promotes the TAMs’ acetate production and secretion. Inhibition of ALDH2 or of lipid peroxidation in TAMs abrogates acetate-induced migration of HCC cells in vitro. In an orthotopic HCC model involving male mice, genetic ablation ofALDH2in TAMs reduces HCC cell acetate levels and HCC lung metastases. Collectively, our findings reveal a metabolic interaction between HCC cells and TAMs—involving lactate, lipid peroxidation and acetate—and position TAMs as an acetate reservoir that drives HCC metastasis. Cancer metabolism Cancer microenvironment Metabolism Metastasis
N Nature Metabolism · Oct 16, 2025 Interaction of sortilin with apolipoprotein E3 enables neurons to use long-chain fatty acids as alternative metabolic fuel Sortilin (SORT1) is a lipoprotein receptor that shows genome-wide association with hypercholesterolaemia, explained by its ability to control hepatic output of lipoproteins. AlthoughSORT1also shows genome-wide association with Alzheimer disease and frontotemporal lobe dementia, the most prevalent forms of age-related dementias, sortilin’s contribution to human brain lipid metabolism and health remains unclear. Here we show that sortilin mediates neuronal uptake of polyunsaturated fatty acids carried by apolipoprotein E (apoE). Using humanized mouse strains and induced pluripotent stem cell-based cell models of brain lipid homeostasis, we demonstrate that internalized lipids are converted into ligands for peroxisome proliferator-activated receptor alpha inducing transcription profiles that enable neurons to use long-chain fatty acids as metabolic fuel when glucose is limited. This pathway works with apoE3 but cannot operate with the Alzheimer disease risk factor apoE4, which disrupts sortilin’s endocytic activity. Our data indicate a role for the lipoprotein receptor sortilin in metabolic fuel choice in neurons, which may be crucial when glucose supply is limited, such as in the ageing brain. Alzheimer's disease Metabolic pathways Metabolism Metabolomics Neuroscience
N Nature Metabolism · Oct 14, 2025 Mitochondrial and psychosocial stress-related regulation of FGF21 in humans Fibroblast growth factor 21 (FGF21) is a metabolic hormone induced by fasting, metabolic stress and mitochondrial oxidative phosphorylation (OxPhos) defects that cause mitochondrial diseases (MitoD). Here we report that acute psychosocial stress alone (without physical exertion) decreases serum FGF21 by an average of 20% (P< 0.0001) in healthy controls, but increases FGF21 by 32% (P< 0.0001) in people with MitoD, pointing to a functional FGF21 interaction between the stress response and OxPhos capacity. We further define co-activation patterns between FGF21 and stress-related neuroendocrine hormones and report associations between FGF21 and psychosocial factors related to stress and wellbeing. Overall, these results highlight a potential role for FGF21 as a stress hormone involved in meeting the energetic needs of psychosocial stress. Diagnostic markers Metabolic diseases Metabolism Mitochondria
N Nature Metabolism · Oct 09, 2025 Early-life ketone body signalling promotes beige fat biogenesis through changes in histone acetylome and β-hydroxybutyrylome Infants undergo distinct ketogenesis during the preweaning period, yet its physiological implications remain unclear. Here, we show that preweaning ketosis promotes beige fat biogenesis and improves health outcomes in adulthood. Loss of ketogenesis in neonatal mice by early weaning or ablation ofHmgcs2hinders beige adipogenesis, subsequently exacerbating metabolic dysregulation in high-fat diet-induced obesity. Enhanced ketogenesis during lactation through exogenous ketone supplements enhances energy expenditure, beige fat formation, and mitochondrial biogenesis and respiration. Using single-cell RNA sequencing, we identified a subset of β-hydroxybutyrate-responsive adipocyte progenitor cells (APCs) expressingCd81that showed high beige adipogenic potential. Enhanced ketogenesis promotes the recruitment of beige APCs and their differentiation into beige adipocytes. Mechanistically, ketogenesis-derived βHB induces a switch in the histone acetylome and β-hydroxybutyrylome for transcriptional activation of beige fat biogenesis genes. Notably, enhanced ketogenesis during lactation alleviates adverse metabolic effects predisposed by parental obesity. Our study highlights that targeting preweaning ketosis to drive beige adipogenesis may offer a therapeutic approach to combat obesity and metabolic diseases in adulthood. Epigenetics Metabolism Mitochondria Obesity Transcriptomics
N Nature Metabolism · Oct 07, 2025 Effect of sweeteners and sweetness enhancers on weight management and gut microbiota composition in individuals with overweight or obesity: the SWEET study Consumption of sweeteners and sweetness enhancers (S&SEs) is a popular strategy to reduce sugar intake, but the role of S&SEs in body weight regulation and gut microbiota composition remains debated. Here, we show that S&SEs in a healthy diet support weight loss maintenance and beneficial gut microbiota shifts in adults with overweight or obesity. In this multi-centre, randomized, controlled trial, we included 341 adults and 38 children with overweight or obesity. Adults followed a 2-month low-energy diet for ≥5% weight loss, followed by a 10-month healthy ad libitum diet with <10% energy from sugars. One group replaced sugar-rich products with S&SE products (S&SEs group), while the other did not (sugar group). Primary outcomes included changes in body weight and gut microbiota composition at 1 year. Secondary outcomes included changes in cardiometabolic parameters. The S&SEs group, compared to the sugar group, maintained greater weight loss at 1 year (1.6 ± 0.7 kg,P= 0.029) and exhibited distinct gut microbiota shifts, with increased short-chain fatty acid and methane-producing taxa (q≤ 0.05). No significant differences were observed in cardiometabolic markers or in children. Overall, our findings indicate that prolonged consumption of S&SEs in a healthy diet is a safe strategy for obesity management. ClinicalTrial.gov identifier:NCT04226911. Obesity Risk factors
N Nature Metabolism · Sep 30, 2025 DDHD2 provides a flux of saturated fatty acids for neuronal energy and function Although fatty acids support mitochondrial ATP production in most tissues, neurons are believed to rely exclusively on glucose for energy. Here we show that genetic ablation of the triglyceride and phospholipid lipaseDdhd2impairs mitochondrial respiration and ATP synthesis in cultured neurons, despite increased glycolysis. This defect arises from reduced levels of long-chain saturated free fatty acids, particularly myristic, palmitic and stearic acids, normally released in an activity-dependent manner by Ddhd2. Inhibition of mitochondrial fatty acid import in wild-type neurons similarly reduced mitochondrial respiration and ATP production. Saturated fatty acyl-coenzyme A treatment restored mitochondrial energy production inDdhd2knockout neurons. When provided in combination, these activated fatty acyl-CoA supplements also rescued defects in membrane trafficking, synaptic function and protein homeostasis. These findings uncover that neurons perform β-oxidation of endogenous long-chain free fatty acids to meet ATP demands and reveal a potential therapeutic strategy for hereditary spastic paraplegia 54 caused byDDHD2mutations. Cellular neuroscience Diseases of the nervous system Learning and memory Metabolism Neurophysiology
N Nature Metabolism · Sep 26, 2025 A non-apoptotic caspase-8–meteorin pathway in hepatocytes promotes MASH fibrosis Metabolic-dysfunction-associated steatohepatitis (MASH) is the leading cause of chronic liver disease, but an incomplete understanding of MASH-induced liver fibrosis has limited therapeutic options. Here we show that hepatocyte caspase-8 drives MASH fibrosis through an apoptosis-independent mechanism. Hepatic caspase-8 expression correlates with liver fibrosis in both human and experimental MASH, and hepatocyte-specific caspase-8 deletion in male mice with MASH suppressed liver fibrosis and hepatic stellate cell (HSC) activation without affecting hepatocyte apoptosis. Mechanistic studies showed that a caspase-8–YY1 pathway in hepatocytes induces secretory meteorin (Metrn), which activates HSCs via a c-Kit–STAT3 pathway. Meteorin expression was increased in human and male mouse MASH livers and decreased by deletion of hepatocyte caspase-8 in MASH mice and human and mouse primary hepatocytes. Genetic restoration of hepatocyte meteorin in hepatocyte-caspase-8-deleted MASH mice restored HSC activation and liver fibrosis while silencing hepatocyte meteorin lowered liver fibrosis. These findings reveal a therapeutically targetable pathway promoting MASH fibrosis involving a non-apoptotic function of caspase-8 and a newly discovered HSC activator, meteorin. Metabolic disorders Metabolism
N Nature Metabolism · Sep 23, 2025 Cholesterol metabolic reprogramming mediates microglia-induced chronic neuroinflammation and hinders neurorestoration following stroke Chronic neuroinflammation is a major obstacle to post-stroke recovery, yet the underlying mechanisms, particularly the link between prolonged microglial activation and cholesterol metabolism, are not fully known. Here we show that ischaemic injury induces persistent microglial activation that perpetuates chronic inflammation, leading to microglial cholesterol accumulation and metabolic reprogramming. Using single-cell RNA sequencing, we identified distinct stroke-associated foamy microglia clusters characterized by extensive reprogramming of cholesterol metabolism. Furthermore, direct intracerebral free cholesterol or cholesterol crystal infusion recapitulated sustained microglial activation, directly linking aberrant cholesterol metabolism to prolonged neuroinflammatory responses. Therapeutically, we demonstrate that reducing microglial cholesterol overload through genetic or pharmacological activation of CYP46A1 in male mice promotes white matter repair and functional recovery. These findings highlight microglial cholesterol metabolism as a key driver of post-stroke inflammation, offering therapeutic strategies targeting cholesterol metabolism to mitigate long-term brain damage and promote neurorestoration, potentially improving stroke-related disability outcomes. Chronic inflammation Homeostasis Metabolism Stroke
N Nature Metabolism · Sep 22, 2025 Slc7a7 licenses macrophage glutaminolysis for restorative functions in atherosclerosis Atherosclerosis is a life-threatening condition characterized by chronic inflammation of the arterial wall. Atherosclerotic plaque macrophages are key players at the site of disease, where metabolic reprogramming dictates the progression of pathogenesis. Here we show that reduced macrophage glutaminase activity is related to glutaminase (GLS)-1 and not GLS2 expression. While glutamine synthetase serves as a metabolic rheostat controlling nutrient flux into cells in vitro, macrophage restorative functions in the context of atherosclerosis relies more heavily on glutamine influx. Enhanced glutamine flux is largely mediated by the SLC7A7 exchanger in macrophages:Slc7a7-silenced macrophages have reduced glutamine influx and GLS1-dependent glutaminolysis, impeding downstream signalling involved in macrophage restorative functions. In vivo, macrophage-specific deletion ofSlc7a7accelerates atherosclerosis in mice with more complex necrotic core composition. Finally, cell-intrinsic regulation of glutaminolysis drives macrophage metabolic and transcriptional rewiring in atherosclerosis by diverting exogenous Gln flux to balance remodelling and restorative functions. Thus, we uncover a role of SLC7A7-dependent glutamine uptake upstream of glutaminolysis in atherosclerotic plaque development and stability. Atherosclerosis Metabolic syndrome Metabolism
N Nature Metabolism · Sep 22, 2025 The Neurolipid Atlas: a lipidomics resource for neurodegenerative diseases Lipid alterations in the brain have been implicated in many neurodegenerative diseases. To facilitate comparative lipidomic research across brain diseases, we establish a data common named the Neurolipid Atlas that we prepopulated with isogenic induced pluripotent stem cell (iPS cell)-derived lipidomics data for different brain diseases. Additionally, the resource contains lipidomics data of human and mouse brain tissue. Leveraging multiple datasets, we demonstrate that iPS cell-derived neurons, microglia and astrocytes exhibit distinct lipid profiles that recapitulate in vivo lipotypes. Notably, the Alzheimer disease (AD) risk gene ApoE4 drives cholesterol ester (CE) accumulation specifically in human astrocytes and we also observe CE accumulation in whole-brain lipidomics from persons with AD. Multiomics interrogation of iPS cell-derived astrocytes revealed that altered cholesterol metabolism has a major role in astrocyte immune pathways such as the immunoproteasome and major histocompatibility complex class I antigen presentation. Our data commons, available online (https://neurolipidatlas.com/), allows for data deposition by the community and provides a user-friendly tool and knowledge base for a better understanding of lipid dyshomeostasis in neurodegenerative diseases. Lipids Metabolism Metabolomics Neuroimmunology Neuroscience
N Nature Metabolism · Sep 19, 2025 Mapping the plasma metabolome to human health and disease in 274,241 adults A systematic characterization of metabolic profiles in human health and disease enhances precision medicine. Here we present a comprehensive human metabolome–phenome atlas, using data from 274,241 UK Biobank participants with nuclear magnetic resonance metabolic measures. This atlas links 313 plasma metabolites to 1,386 diseases and 3,142 traits, with participants being prospectively followed for a median of 14.9 years. This atlas uncovered 52,836 metabolite–disease and 73,639 metabolite–trait associations, where the ratio of cholesterol to total lipids in large low-density lipoprotein percentage was found as the metabolite associated with the highest number (n= 526) of diseases. In addition, we found that more than half (57.5%) of metabolites showed statistical variations from healthy individuals over a decade before disease onset. Combined with demographics, the machine-learning-based metabolic risk score signified the top 30 (around 10%) metabolites as biomarkers, yielding favourable classification performance (area under the curve > 0.8) for 94 prevalent and 81 incident diseases. Finally, Mendelian randomization analyses provided support for causal relationships of 454 metabolite–disease pairs, among which 402 exhibited shared genetic determinants. Additional insights can be gleaned via an accessible interactive resource (https://metabolome-phenome-atlas.com/). Biomarkers Diseases Metabolism Translational research
N Nature Metabolism · Sep 19, 2025 Fructose and glucose from sugary drinks enhance colorectal cancer metastasis via SORD The consumption of sugar-sweetened beverages (SSBs), which contain high levels of fructose and glucose, has been causally and mechanistically linked to an increased risk of colorectal cancer (CRC). However, the effects of SSB consumption on advanced stages of disease progression, including metastasis, remain poorly understood. Here we show that exposure of CRC cells to a glucose and fructose formulation—reflecting the composition of both high-fructose corn syrup and sucrose found in SSBs—enhances cellular motility and metastatic potential compared to glucose alone. Given that CRC cells grow poorly in fructose alone, and cells in vivo are not physiologically exposed to fructose without glucose, we excluded the fructose-only condition from our studies unless needed as a control. Mechanistically, the combination of glucose and fructose elevates the NAD⁺/NADH ratio by activation of the reverse reaction of sorbitol dehydrogenase in the polyol pathway. This redox shift relieves NAD⁺ limitations and accelerates glycolytic activity, which in turn fuels activation of the mevalonate pathway, ultimately promoting CRC cell motility and metastasis. Our findings highlight the detrimental impact of SSBs on CRC progression and suggest potential dietary and therapeutic strategies to mitigate metastasis in patients with CRC. Cancer metabolism Colorectal cancer Metabolism Metabolomics
N Nature Metabolism · Sep 18, 2025 Redox-dependent liver gluconeogenesis impacts different intensity exercise in mice Hepatic gluconeogenesis produces glucose from various substrates to meet energy demands. However, how these substrates are preferentially used under different conditions remains unclear. Here, we show that preferential supplies of lactate and glycerol modulate hepatic gluconeogenesis, thereby impacting high-intensity and low-intensity exercise capacities, respectively. We find that liver-specific knockout of phosphoenolpyruvate carboxykinase 1 (L-Pck1KO), which blocks gluconeogenesis from lactate, decreases high-intensity exercise capacity but increases low-intensity exercise capacity by enhancing gluconeogenesis from glycerol. Conversely, liver-specific knockout of glycerol kinase (L-GykKO), which inhibits glycerol-derived gluconeogenesis, induces the opposite effects by enhancing gluconeogenesis from lactate. Given that these compensatory steps depend on NAD+-mediated oxidation in the cytosol, we hepatically expressed NADH oxidase fromLactobacillus brevis(LbNOX) to decrease the cytosolic [NADH]/[NAD+] ratio. We find that hepatic LbNOX expression enhances gluconeogenesis from both redox-dependent substrates and increases exercise capacities at both intensities. Importantly, LbNOX-induced enhancement of high-intensity and low-intensity exercise capacities is abolished in L-Pck1KO and L-GykKO mice, respectively. Therefore, supplies of gluconeogenic substrates and cytosolic redox states, rather than altered enzyme expressions, modulate hepatic gluconeogenesis and exercise capacity at different intensities. Globally, this study shows that regulating hepatic gluconeogenesis through cytosolic redox states is a potent strategy for increasing exercise performance. Biochemistry Carbohydrates Metabolism
N Nature Metabolism · Sep 17, 2025 Metabolic variation reflects dietary exposure in a multi-ethnic Asian population Understanding how diet shapes metabolism across diverse populations is essential to improving nutrition and health. Biomarkers reflecting diet are explored largely in European and American populations, but the food metabolome is highly complex and varies across region and culture. We assessed 1,055 plasma metabolites and 169 foods/beverages in 8,391 multi-ethnic Asian individuals and carried out diet–metabolite association analyses. Using machine learning, we developed multi-biomarker panels and composite scores for key foods, beverages and overall diet quality. Here we show these biomarker panels can be used to objectively assess dietary intakes in the Asian multi-ethnic population and can explain variances in intake prediction models better than single biomarkers. The identified diet–metabolite relationships are reproducible over time and improve prediction of clinical outcomes (insulin resistance, diabetes, body mass index, carotid intima-media thickness and hypertension), compared to self-reports. Our findings show insights into multi-ethnic diet-related metabolic variations and an opportunity to link exposure to population health outcomes. Biomarkers Metabolism Metabolomics Nutrition Risk factors
N Nature Metabolism · Sep 16, 2025 BDH2-driven lysosome-to-mitochondria iron transfer shapes ferroptosis vulnerability of the melanoma cell states Iron sustains cancer cell plasticity, yet it also sensitizes the mesenchymal, drug-tolerant phenotype to ferroptosis. This posits that iron compartmentalization must be tightly regulated. However, the molecular machinery governing organelle Fe(II) compartmentalization remains elusive. Here, we show that BDH2 is a key effector of inter-organelle Fe(II) redistribution and ferroptosis vulnerability during melanoma transition from a melanocytic (MEL) to a mesenchymal-like (MES) phenotype. In MEL cells, BDH2 localizes at the mitochondria–lysosome contacts (MLCs) to generate the siderophore 2,5-dihydroxybenzoic acid (2,5-DHBA), which ferries iron into the mitochondria. Fe(II) transfer by BDH2 supports mitochondrial bioenergetics, which is required to maintain lysosomal acidification and MLC formation. Loss of BDH2 alters lysosomal pH and MLC tethering dynamics, causing lysosomal iron sequestration, which primes MES cells for ferroptosis. Rescuing BDH2 expression, or supplementing 2,5-DHBA, rectifies lysosomal pH and MLCs, protecting MES cells from ferroptosis and enhancing their ability to metastasize. Thus, we unveil a BDH2-dependent mechanism that orchestrates inter-organelle Fe(II) transfer, linking metabolic regulation of lysosomal pH to the ferroptosis vulnerability of the mesenchymal, drug-tolerant cancer cells. Cancer metabolism Cell death Lysosomes Metabolism Mitochondria
N Nature Metabolism · Sep 16, 2025 Lac-Phe induces hypophagia by inhibiting AgRP neurons in mice N-Lactoyl-phenylalanine (Lac-Phe) is a lactate-derived circulating metabolite that reduces feeding and obesity, but the molecular mechanisms that underlie the metabolic benefits of Lac-Phe remain unknown. Here we show that Lac-Phe directly inhibits hypothalamic neurons that express Agouti-related protein (AgRP), resulting in an indirect activation of anorexigenic neurons in the paraventricular nucleus of the hypothalamus (PVH). Both AgRP inhibition and PVH activation are required to mediate Lac-Phe-induced hypophagia. Lac-Phe-mediated inhibition of AgRP neurons occurs through activation of the ATP-sensitive potassium (KATP) channel, whereas inhibition of the KATPchannel blunts the effects of Lac-Phe to suppress feeding. Together, these results reveal the molecular and neurobiological mechanisms by which Lac-Phe mediates metabolic improvements and suggest this exercise-induced metabolite might have therapeutic benefits in various human diseases. Hypothalamus Neurophysiology
N Nature Metabolism · Sep 15, 2025 Dietary fibre-adapted gut microbiome clears dietary fructose and reverses hepatic steatosis Excessive consumption of the simple sugar fructose, which induces excessive hepatic lipogenesis and gut dysbiosis, is a risk factor for cardiometabolic diseases. Here we show in male mice that the gut microbiome, when adapted to dietary fibre inulin, catabolizes dietary fructose and mitigates or reverses insulin resistance, hepatic steatosis and fibrosis. Specifically, inulin supplementation, without affecting the host’s small intestinal fructose catabolism, promotes the small intestinal microbiome to break down incoming fructose, thereby decreasing hepatic lipogenesis and fructose spillover to the colonic microbiome. Inulin also activates hepatic de novo serine synthesis and cystine uptake, augmenting glutathione production and protecting the liver from fructose-induced lipid peroxidation. These multi-modal effects of inulin are transmittable by the gut microbiome, whereBacteroides acidifaciensacts as a key player. Thus, the gut microbiome, adapted to use inulin (a fructose polymer), efficiently catabolizes dietary monomeric fructose, thereby protecting the host. These findings provide a mechanism for how fibre can facilitate the gut microbiome to mitigate the host’s exposure to harmful nutrients and disease progression. Liver Metabolism Metabolomics Microbiota Small intestine
N Nature Metabolism · Sep 10, 2025 In vivo itaconate tracing reveals degradation pathway and turnover kinetics Itaconate is an immunomodulatory metabolite that alters mitochondrial metabolism and immune cell function. This organic acid is endogenously synthesized by tricarboxylic acid (TCA) metabolism downstream of TLR signalling. Itaconate-based treatment strategies are under investigation to mitigate numerous inflammatory conditions. However, little is known about the turnover rate of itaconate in circulation, the kinetics of its degradation and the broader consequences on metabolism. By combining mass spectrometry and in vivo13C itaconate tracing in male mice, we demonstrate that itaconate is rapidly eliminated from plasma, excreted via urine and fuels TCA cycle metabolism specifically in the liver and kidneys. Our results further reveal that itaconate is converted into acetyl-CoA, mesaconate and citramalate. Itaconate administration also influences branched-chain amino acid metabolism and succinate levels, indicating a functional impact on succinate dehydrogenase and methylmalonyl-CoA mutase activity in male rats and mice. Our findings uncover a previously unknown aspect of itaconate metabolism, highlighting its rapid catabolism in vivo that contrasts findings in cultured cells. Biochemistry Cell biology Metabolism Physiology
N Nature Metabolism · Sep 09, 2025 Cellular pan-chain acyl-CoA profiling reveals SLC25A42/SLC25A16 in mitochondrial CoA import and metabolism The essential cofactor coenzyme A (CoASH) and its thioester derivatives (acyl-CoAs) have pivotal roles in cellular metabolism. However, the mechanism by which different acyl-CoAs are accurately partitioned into different subcellular compartments to support site-specific reactions, and the physiological impact of such compartmentalization, remain poorly understood. Here, we report an optimized liquid chromatography–mass spectrometry-based pan-chain acyl-CoA extraction and profiling method that enables a robust detection of 33 cellular and 23 mitochondrial acyl-CoAs from cultured human cells. We reveal that SLC25A16 and SLC25A42 are critical for mitochondrial import of free CoASH. This CoASH import process supports an enriched mitochondrial CoA pool and CoA-dependent pathways in the matrix, including the high-flux TCA cycle and fatty acid oxidation. Despite a small fraction of the mitochondria-localized CoA synthase COASY, de novo CoA biosynthesis is primarily cytosolic and supports cytosolic lipid anabolism. This mitochondrial acyl-CoA compartmentalization enables a spatial regulation of anabolic and energy-related catabolic processes, which promises to shed light on pathophysiology in the inborn errors of CoA metabolism. Biochemistry Metabolism Mitochondria Organelles
N Nature Metabolism · Sep 09, 2025 Common genetic variants modify disease risk and clinical presentation in monogenic diabetes Young-onset monogenic disorders often show variable penetrance, yet the underlying causes remain poorly understood. Uncovering these influences could reveal new biological mechanisms and enhance risk prediction for monogenic diseases. Here we show that polygenic background substantially shapes the clinical presentation of maturity-onset diabetes of the young (MODY), a common monogenic form of diabetes that typically presents in adolescence or early adulthood. We find strong enrichment of type 2 diabetes (T2D) polygenic risk, but not type 1 diabetes risk, in genetically confirmed MODY cases (n= 1,462). This T2D polygenic burden, primarily through beta-cell dysfunction pathways, is strongly associated with earlier age of diagnosis and increased diabetes severity. Common genetic variants collectively account for 24% (P< 0.0001) of the phenotypic variability. Using a large population cohort (n= 424,553), we demonstrate that T2D polygenic burden substantially modifies diabetes onset in individuals with pathogenic variants, with diabetes risk ranging from 11% to 81%. Finally, we show that individuals with MODY-like phenotypes (n= 300) without a causal variant have elevated polygenic burden for T2D and related traits, representing potential polygenic phenocopies. These findings reveal substantial influence of common genetic variation in shaping the clinical presentation of early-onset monogenic disorders. Incorporating these may improve risk estimates for individuals carrying pathogenic variants. Diabetes Endocrine system and metabolic diseases Genetics Genomics Metabolism
N Nature Metabolism · Sep 08, 2025 An alternative route for β-hydroxybutyrate metabolism supports cytosolic acetyl-CoA synthesis in cancer cells Cancer cells are exposed to diverse metabolites in the tumour microenvironment that are used to support the synthesis of nucleotides, amino acids and lipids needed for rapid cell proliferation. In some tumours, ketone bodies such as β-hydroxybutyrate (β-OHB), which are elevated in circulation under fasting conditions or low glycemic diets, can serve as an alternative fuel that is metabolized in the mitochondria to provide acetyl-CoA for the tricarboxylic acid (TCA) cycle. Here we identify a non-canonical route for β-OHB metabolism that bypasses the TCA cycle to generate cytosolic acetyl-CoA. We show that in cancer cells that can metabolize ketones, β-OHB-derived acetoacetate in the mitochondria can be shunted into the cytosol, where acetoacetyl-CoA synthetase (AACS) and thiolase convert it into cytosolic acetyl-CoA. This alternative metabolic routing allows β-OHB to avoid oxidation in the mitochondria and to be used as a major source of cytosolic acetyl-CoA, even when other key cytosolic acetyl-CoA precursors such as glucose are available in excess. Finally, we demonstrate that ketone body metabolism, including this alternative AACS-dependent route, can support the growth of mouseKrasG12D;Trp53−/−pancreatic tumours grown orthotopically in the pancreas of male mice, as well as the growth of mouse B16 melanoma tumours in male mice fed a calorie-restricted diet. Together, these data reveal how cancer cells use β-OHB as a major source of cytosolic acetyl-CoA to support cell proliferation and tumour growth. Cancer metabolism Cancer microenvironment Lipids Metabolism
N Nature Metabolism · Aug 27, 2025 ATF6 activation alters colonic lipid metabolism causing tumour-associated microbial adaptation The transcription factor ATF6 causes an enrichment in long-chain fatty acids in the colonic epithelium, which leads to changes in the gut microbiota and contributes to the development of colorectal cancer in humans and mice, thereby linking endoplasmic reticulum stress responses to lipid metabolism and tumorigenesis.
N Nature Metabolism · Aug 22, 2025 Targeting MondoA–TXNIP restores antitumour immunity in lactic-acid-induced immunosuppressive microenvironment In the tumour microenvironment, accumulated lactic acid (LA) promotes tumour immune evasion by facilitating regulatory T cell (Treg) immunosuppressive function and restraining CD8+T cell cytotoxicity, but the underlying mechanism remains elusive. Here we report that transcriptional factor MondoA-induced thioredoxin interacting protein (TXNIP) transcription is a common feature of both Tregand CD8+T cells in response to lactic acid. In contrast to reduction in immunosuppressive capacity inMondoA-deficient Tregcells, loss of MondoA enhanced CD8+T cell cytotoxic function in the lactic-acid-induced immunosuppressive microenvironment, by restoring glucose uptake and glycolysis. Mechanistically, lactic acid relied on sentrin/SUMO-specific protease 1 (SENP1) to stimulate the MondoA–TXNIP axis, which impaired TCR/CD28-signal-induced CD8+T cell activation. Importantly, targeting the MondoA–TXNIP axis potentiated antitumour immunity in multiple cancer types and synergized with anti-PD-1 therapy to promote effective T cell responses in colorectal cancer. Our results demonstrate that the MondoA–TXNIP axis is a promising therapeutic target for improving cancer immunotherapy. Cancer immunotherapy Cancer metabolism Cancer microenvironment Immunoediting Metabolism
N Nature Metabolism · Aug 19, 2025 Fluorescent GLP1R/GIPR dual agonist probes reveal cell targets in the pancreas and brain Dual agonists targeting glucagon-like peptide-1 receptor (GLP1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) are breakthrough treatments for patients with type 2 diabetes and obesity. Compared to GLP1R agonists, dual agonists show superior efficacy for glucose lowering and weight reduction. However, delineation of dual agonist cell targets remains challenging. Here, we develop and test daLUXendin and daLUXendin+, non-lipidated and lipidated fluorescent GLP1R/GIPR dual agonist probes, and use them to visualize cellular targets. daLUXendins are potent GLP1R/GIPR dual agonists that advantageously show less functional selectivity for mouse GLP1R over mouse GIPR. daLUXendins label rodent and human pancreatic islet cells, with a signal intensity of β cells > α cells = δ cells. Systemic administration of daLUXendin strongly labels GLP1R+and GIPR+neurons in circumventricular organs characterized by an incomplete blood–brain barrier but does not penetrate the brain beyond labelling seen with single (ant)agonists. At the single-molecule level, daLUXendin targets endogenous GLP1R–GIPR nanodomains, which differ in organization and composition from those targeted by a single agonist. daLUXendins reveal dual agonist targets in the pancreas and brain and exclude a role for brain penetration in determining the superior efficacy of dual agonists, shedding new light on different modes of action of dual agonists versus single agonists. Obesity Receptor pharmacology Super-resolution microscopy Type 2 diabetes
