Pub Date : 2026-01-28DOI: 10.1038/s42255-025-01447-y
{"title":"Identifying genes and proteins with causal effects on type 2 diabetes risk across tissues and populations.","authors":"","doi":"10.1038/s42255-025-01447-y","DOIUrl":"https://doi.org/10.1038/s42255-025-01447-y","url":null,"abstract":"","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"42 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146069972","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-28DOI: 10.1038/s42255-025-01443-2
Yinuo Wang, Haojie Shi, Janina Wittig, Yonggang Ren, Julio Cordero, Matthias Dewenter, Jessica Mella, Abigail Buchwalter, Johannes Backs, Thomas Wieland, Joerg Heineke, Ingrid Fleming, Sofia-Iris Bibli, Gergana Dobreva
Spatiotemporal changes in the nuclear lamina and cell metabolism shape cell fate, yet their interplay is poorly understood. Here we identify lamin A/C as a key regulator of cysteine catabolic flux essential for proper cell fate and longevity. Its loss in naive mouse pluripotent stem cells leads to upregulation of the cysteine-generating and catabolizing enzymes, cystathionine γ-lyase (CTH) and cystathionine β-synthase (CBS), thereby promoting de novo cysteine synthesis. Increased cysteine flux into acetyl-CoA fosters histone H3K9 and H3K27 acetylation, triggering a transition from naive to primed pluripotency and abnormal cell fate and function. Conversely, the toxic gain-of-function mutation of Lmna, encoding lamin A/C and associated with premature ageing, reduces CTH and CBS levels. This reroutes cysteine catabolic flux and alters the balance between H3K9 acetylation and methylation, crucially impacting germ layer formation and genome stability. Notably, modulation of Cth and Cbs rescues the abnormal cell fate and function, restores the DNA damage repair capacity and alleviates the senescent phenotype caused by lamin A/C mutations, highlighting the potential of modulating cell metabolism to mitigate epigenetic diseases.
{"title":"Lamin A/C-regulated cysteine catabolic flux modulates stem cell fate through epigenome reprogramming","authors":"Yinuo Wang, Haojie Shi, Janina Wittig, Yonggang Ren, Julio Cordero, Matthias Dewenter, Jessica Mella, Abigail Buchwalter, Johannes Backs, Thomas Wieland, Joerg Heineke, Ingrid Fleming, Sofia-Iris Bibli, Gergana Dobreva","doi":"10.1038/s42255-025-01443-2","DOIUrl":"https://doi.org/10.1038/s42255-025-01443-2","url":null,"abstract":"Spatiotemporal changes in the nuclear lamina and cell metabolism shape cell fate, yet their interplay is poorly understood. Here we identify lamin A/C as a key regulator of cysteine catabolic flux essential for proper cell fate and longevity. Its loss in naive mouse pluripotent stem cells leads to upregulation of the cysteine-generating and catabolizing enzymes, cystathionine γ-lyase (CTH) and cystathionine β-synthase (CBS), thereby promoting de novo cysteine synthesis. Increased cysteine flux into acetyl-CoA fosters histone H3K9 and H3K27 acetylation, triggering a transition from naive to primed pluripotency and abnormal cell fate and function. Conversely, the toxic gain-of-function mutation of Lmna, encoding lamin A/C and associated with premature ageing, reduces CTH and CBS levels. This reroutes cysteine catabolic flux and alters the balance between H3K9 acetylation and methylation, crucially impacting germ layer formation and genome stability. Notably, modulation of Cth and Cbs rescues the abnormal cell fate and function, restores the DNA damage repair capacity and alleviates the senescent phenotype caused by lamin A/C mutations, highlighting the potential of modulating cell metabolism to mitigate epigenetic diseases.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"21 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146057204","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-27DOI: 10.1038/s42255-025-01444-1
Ozvan Bocher, Ana Luiza Arruda, Satoshi Yoshiji, Chi Zhao, Alicia Huerta-Chagoya, Chen-Yang Su, Xianyong Yin, Davis Cammann, Henry J. Taylor, Jingchun Chen, Ken Suzuki, Ravi Mandla, Ta-Yu Yang, Fumihiko Matsuda, Josep M. Mercader, Jason Flannick, James B. Meigs, Alexis C. Wood, Marijana Vujkovic, Benjamin F. Voight, Cassandra N. Spracklen, Jerome I. Rotter, Andrew P. Morris, Eleftheria Zeggini
Type 2 diabetes (T2D) is a prevalent disease arising from complex molecular mechanisms. Here we leverage T2D genetic associations to identify causal molecular mechanisms in an ancestry-aware and tissue-aware manner. Using two-sample Mendelian randomization corroborated by colocalization across four global ancestries, we analyse 20,307 gene and 1,630 protein expression levels using blood-derived cis-quantitative trait loci (QTLs). We detect causal effects of genetically predicted levels of 335 genes and 46 proteins on T2D risk, with 16.4% and 50% replication in independent cohorts, respectively. Using gene expression cis-QTLs derived from seven T2D-relevant tissues, we identify causal links between the expression of 676 genes and T2D risk, refining known associations such as BAK1 and describing additional ones like CPXM1. Causal effects are mostly shared across ancestries but are highly heterogeneous across tissues. Our findings provide insights into cross-ancestry and tissue-informed multi-omics causal inference approaches and demonstrate their power in uncovering molecular processes driving T2D.
{"title":"Unravelling the molecular mechanisms causal to type 2 diabetes across global populations and disease-relevant tissues","authors":"Ozvan Bocher, Ana Luiza Arruda, Satoshi Yoshiji, Chi Zhao, Alicia Huerta-Chagoya, Chen-Yang Su, Xianyong Yin, Davis Cammann, Henry J. Taylor, Jingchun Chen, Ken Suzuki, Ravi Mandla, Ta-Yu Yang, Fumihiko Matsuda, Josep M. Mercader, Jason Flannick, James B. Meigs, Alexis C. Wood, Marijana Vujkovic, Benjamin F. Voight, Cassandra N. Spracklen, Jerome I. Rotter, Andrew P. Morris, Eleftheria Zeggini","doi":"10.1038/s42255-025-01444-1","DOIUrl":"https://doi.org/10.1038/s42255-025-01444-1","url":null,"abstract":"Type 2 diabetes (T2D) is a prevalent disease arising from complex molecular mechanisms. Here we leverage T2D genetic associations to identify causal molecular mechanisms in an ancestry-aware and tissue-aware manner. Using two-sample Mendelian randomization corroborated by colocalization across four global ancestries, we analyse 20,307 gene and 1,630 protein expression levels using blood-derived cis-quantitative trait loci (QTLs). We detect causal effects of genetically predicted levels of 335 genes and 46 proteins on T2D risk, with 16.4% and 50% replication in independent cohorts, respectively. Using gene expression cis-QTLs derived from seven T2D-relevant tissues, we identify causal links between the expression of 676 genes and T2D risk, refining known associations such as BAK1 and describing additional ones like CPXM1. Causal effects are mostly shared across ancestries but are highly heterogeneous across tissues. Our findings provide insights into cross-ancestry and tissue-informed multi-omics causal inference approaches and demonstrate their power in uncovering molecular processes driving T2D.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"4 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146057217","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-21DOI: 10.1038/s42255-025-01439-y
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. A pathogenic subset of NK cells is identified that promotes type 1 diabetes and is generated via T cell-derived IL-21.
{"title":"IL-21 mediates crosstalk between T cells and NK cells during the remission of type 1 diabetes","authors":"Kang Lei, Xinyu Li, Ting Zhong, Rong Tang, Qiaolin Deng, Paul E. Love, Zhiguang Zhou, Bin Zhao, Xia Li","doi":"10.1038/s42255-025-01439-y","DOIUrl":"10.1038/s42255-025-01439-y","url":null,"abstract":"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. A pathogenic subset of NK cells is identified that promotes type 1 diabetes and is generated via T cell-derived IL-21.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 1","pages":"177-195"},"PeriodicalIF":20.8,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146006252","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-20DOI: 10.1038/s42255-025-01429-0
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.
{"title":"Distinct sympathetic projections to brown fat regulate thermogenesis and glucose tolerance.","authors":"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","doi":"10.1038/s42255-025-01429-0","DOIUrl":"https://doi.org/10.1038/s42255-025-01429-0","url":null,"abstract":"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.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"30 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-20DOI: 10.1038/s42255-025-01435-2
Xun Huang,Li Ye
{"title":"Heterogeneous sympathetic control of brown adipose tissue.","authors":"Xun Huang,Li Ye","doi":"10.1038/s42255-025-01435-2","DOIUrl":"https://doi.org/10.1038/s42255-025-01435-2","url":null,"abstract":"","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"39 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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. Psychological stress-mediated dysregulation of catecholamine signalling rewires the hepatic kynurenine pathway, which in turn impairs liver CD8+ T cell function and promotes liver cancer progression.
{"title":"Chronic stress drives liver cancer by impairing the hepatic kynurenine pathway and immune surveillance","authors":"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","doi":"10.1038/s42255-025-01430-7","DOIUrl":"10.1038/s42255-025-01430-7","url":null,"abstract":"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. Psychological stress-mediated dysregulation of catecholamine signalling rewires the hepatic kynurenine pathway, which in turn impairs liver CD8+ T cell function and promotes liver cancer progression.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 1","pages":"196-214"},"PeriodicalIF":20.8,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146003854","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-19DOI: 10.1038/s42255-025-01446-z
Gerard Clarke, Lily Keane, John F. Cryan
In this issue of Nature Metabolism, Sun et al. show that the kynurenine pathway of tryptophan metabolism links stress-induced impairment of immune surveillance to liver cancer progression.
{"title":"Hepatic tryptophan metabolism links chronic stress to liver cancer","authors":"Gerard Clarke, Lily Keane, John F. Cryan","doi":"10.1038/s42255-025-01446-z","DOIUrl":"10.1038/s42255-025-01446-z","url":null,"abstract":"In this issue of Nature Metabolism, Sun et al. show that the kynurenine pathway of tryptophan metabolism links stress-induced impairment of immune surveillance to liver cancer progression.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 1","pages":"10-11"},"PeriodicalIF":20.8,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146003887","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-16DOI: 10.1038/s42255-025-01428-1
Kimberly S. Huggler, Kyle M. Flickinger, Matthew H. Forsberg, Carlos A. Mellado Fritz, Gavin R. Chang, Meghan F. McGuire, Christian M. Capitini, Jason R. Cantor
Hexokinase (HK) catalyses the phosphorylation of glucose to glucose 6-phosphate, marking the first step of glucose metabolism. Most cancer cells co-express two homologous HK isoforms, HK1 and HK2, which can each bind the outer mitochondrial membrane (OMM). CRISPR screens performed across hundreds of cancer cell lines indicate that both isoforms are dispensable for growth in conventional culture media. By contrast, HK2 deletion impaired cell growth in human plasma-like medium. Here we show that this conditional HK2 dependence can be traced to the subcellular distribution of HK1. Notably, OMM-detached (cytosolic) rather than OMM-docked HK supports cell growth and aerobic glycolysis (the Warburg effect), an enigmatic phenotype of most proliferating cells. We show that under conditions promoting increased translocation of HK1 to the OMM, HK2 is required for cytosolic HK activity to sustain this phenotype, thereby driving sufficient glycolytic ATP production. Our results reveal a basis for conditional HK2 essentiality and suggest that demand for compartmentalized ATP synthesis explains why cells engage in aerobic glycolysis. Hexokinase detachment from the outer mitochondrial membrane is shown to support aerobic glycolysis in cancer cells. Differential localization of the HK1 isoform to the outer mitochondrial membrane, compared to the HK2 isoform, explains the conditional essentiality of HK2 in cancer cells cultured in physiologic media.
{"title":"Hexokinase detachment from mitochondria drives the Warburg effect to support compartmentalized ATP production","authors":"Kimberly S. Huggler, Kyle M. Flickinger, Matthew H. Forsberg, Carlos A. Mellado Fritz, Gavin R. Chang, Meghan F. McGuire, Christian M. Capitini, Jason R. Cantor","doi":"10.1038/s42255-025-01428-1","DOIUrl":"10.1038/s42255-025-01428-1","url":null,"abstract":"Hexokinase (HK) catalyses the phosphorylation of glucose to glucose 6-phosphate, marking the first step of glucose metabolism. Most cancer cells co-express two homologous HK isoforms, HK1 and HK2, which can each bind the outer mitochondrial membrane (OMM). CRISPR screens performed across hundreds of cancer cell lines indicate that both isoforms are dispensable for growth in conventional culture media. By contrast, HK2 deletion impaired cell growth in human plasma-like medium. Here we show that this conditional HK2 dependence can be traced to the subcellular distribution of HK1. Notably, OMM-detached (cytosolic) rather than OMM-docked HK supports cell growth and aerobic glycolysis (the Warburg effect), an enigmatic phenotype of most proliferating cells. We show that under conditions promoting increased translocation of HK1 to the OMM, HK2 is required for cytosolic HK activity to sustain this phenotype, thereby driving sufficient glycolytic ATP production. Our results reveal a basis for conditional HK2 essentiality and suggest that demand for compartmentalized ATP synthesis explains why cells engage in aerobic glycolysis. Hexokinase detachment from the outer mitochondrial membrane is shown to support aerobic glycolysis in cancer cells. Differential localization of the HK1 isoform to the outer mitochondrial membrane, compared to the HK2 isoform, explains the conditional essentiality of HK2 in cancer cells cultured in physiologic media.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"8 1","pages":"215-236"},"PeriodicalIF":20.8,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145990090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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