bims-obesme 2026-11-01 papers

bims-obesme

Biomed News

on Obesity metabolism

Issue of 2026–11–01
thirteen papers selected by
Xiong Weng, University of Edinburgh

Single-cell landscape of human adipose tissue reveals THBS1 as a potential driver of fibro-inflammation in metabolic disease.
An Adipocyte MKK3-p38β Axis Preserves Insulin Responsiveness in Mice and Is Reciprocally Altered in Human Obesity.
Population-scale single-nucleus multi-omic profiling of skeletal muscle reveals extensive context-specific genetic regulation.
Manipulation of ER-mitochondria interactions with mitofusin modulators reduces cardiac damage during myocardial infarction in mice.
Mitochondrial DNA replication and genome stability: From mechanisms to therapeutic strategies.
Lactate Drives Pathological Browning of White Adipose Tissue to Aggravate Sepsis-Associated Metabolic Disorders in a GPR81-Dependent Manner.
Genetic variants shape single-cell chromatin accessibility and disease risk.
Systematic mapping of enhancers, silencers, and topological elements with prime editing deletion screens.
MetabDB: an integrated resource for human metabolic measures, disease associations, and genetic evidence.
The AMPK signaling pathway in cell metabolism and human diseases.
An epigenetic aging-informed dietary pattern is associated with a spectrum of aging-related health outcomes.
Inhibition of lactate-histone lactylation mediated cardiomyocyte-fibroblast communication mitigates cardiac fibrosis in cardiomyopathy models with Hippo pathway activation.
Rare and common genetic variants shape single-cell immune gene expression.

Nat Commun. 2026 Oct 27. pii: 11136. [Epub ahead of print]17(1):

Single-cell landscape of human adipose tissue reveals THBS1 as a potential driver of fibro-inflammation in metabolic disease.

Jisu Jung, Eun Seo Park, Na Keum Lee, Jung-Jae Lee, Uijin Juang, Qingzhi Huang, Young Suk Park, Hyung Joon Kim, Jung-Kwon Kim, Tae Jung Oh, Jae Myoung Suh, Jae Bum Kim, Joon Ho Moon, Jong Kyoung Kim, Sung Hee Choi.

The cellular complexity of adipose tissue plays a critical role in the pathogenesis of metabolic disease; however, mechanisms underlying adipose dysfunction remain poorly understood. Here, we constructed a single-nucleus and bulk transcriptomic atlas of human visceral adipose tissues from an ethnically homogeneous cohort with defined metabolic states: lean with normal glucose tolerance, obesity, and obesity with type 2 diabetes. Single-nucleus RNA sequencing (snRNA-seq) revealed a fibro-inflammatory subpopulation of adipose stem cells and adipocytes characterized by high THBS1 expression, which were enriched in individuals with obesity and obesity with type 2 diabetes compared to lean controls. Through complementary in vitro (human primary ASCs, THP-1 macrophages, and Matrigel-captured mature adipocytes), ex vivo (mouse and human visceral adipose tissue explants), and in vivo (gain-of-function and antibody-mediated neutralization) experiments, we demonstrated that THBS1 promoted adipose fibrosis and inflammation via macrophage-mediated TGFβ activation, impairing adipogenesis and adipocyte function. Inhibition of THBS1 attenuated fibro-inflammatory features in metabolically dysfunctional adipose tissues. Moreover, THBS1 levels in plasma and adipocytes correlated with metabolic traits, including BMI and HbA1c. Collectively, our study provides a cellular atlas of human visceral adipose tissues across metabolic disease states and identifies THBS1 as a key pathogenic driver and potential therapeutic target.

DOI: https://doi.org/10.1038/s41467-026-77107-w
Adv Sci (Weinh). 2026 Oct 28. pii: e20388. [Epub ahead of print]

An Adipocyte MKK3-p38β Axis Preserves Insulin Responsiveness in Mice and Is Reciprocally Altered in Human Obesity.

Edgar Bernardo, Nuria Matesanz, Jorge-Luis Torres, Alba C Arcones, Juan Ignacio Jiménez-Loygorri, Alfonso Mora, Leticia Herrera-Melle, Luis Leiva-Vega, Maria Elena Rodriguez, Lourdes Hernández-Cosido, Marta Leon, Paula Yong González, Teresa Durán, Tamara Parracho, Francisca Mulero, Rubén Nogueiras, J Simon C Arthur, Angel R Nebreda, Roger J Davis, Miguel Marcos, Guadalupe Sabio.

  Obesity is a major risk factor for insulin resistance and type 2 diabetes. Adipocyte stress responses can either promote metabolic dysfunction or preserve insulin action, but the contribution of the p38 MAPK activator MKK3 to adipose tissue physiology remains poorly understood. Here, we show that adipose MKK3 expression increases early during high-fat feeding and is also elevated in human obesity. In human visceral adipose tissue, MKK3 expression was positively associated with body mass index and leptin and inversely associated with HbA1c in unadjusted analyses. Using germline, Fabp4-Cre, and Adipo-Cre Mkk3-deficient mice, together with p38β-deficient mice and primary adipocytes, we found that loss of adipocyte MKK3 impairs insulin responsiveness. Adipo-Cre;Mkk3fl/fl (AdipoMkk3) mice displayed reduced insulin-stimulated glucose uptake selectively in subcutaneous white adipose tissue despite unchanged body composition and basal brown adipose tissue activity. Mechanistically, MKK3 or p38β deficiency increased p70S6K activity and inhibitory IRS1 Ser307 phosphorylation, reduced GLUT4 translocation and Akt activation, and these defects were partially rescued by rapamycin or the selective p70S6K inhibitor PF-4708671. Together, these findings identify an adipocyte MKK3-p38β-p70S6K axis that helps preserve insulin signaling during nutritional stress.

Keywords:  MKK3/p38β signaling; adipocytes; insulin resistance; obesity; type 2 diabetes mellitus

DOI:  https://doi.org/10.1002/advs.202520388
Nat Genet. 2026 Oct 28.

Population-scale single-nucleus multi-omic profiling of skeletal muscle reveals extensive context-specific genetic regulation.

Arushi Varshney, Nandini Manickam, Peter Orchard, Adelaide Tovar, Christa Ventresca, Zhenhao Zhang, Fan Feng, Joseph Mears, Michael R Erdos, Narisu Narisu, Kirsten Nishino, Vivek Rai, Heather M Stringham, Anne U Jackson, Tricia Tamsen, Chao Gao, Mao Yang, Olivia I Koues, Joshua D Welch, Charles F Burant, L Keoki Williams, Chris Jenkinson, Ralph A DeFronzo, Luke Norton, Jouko Saramies, Timo A Lakka, Markku Laakso, Jaakko Tuomilehto, Karen L Mohlke, Jacob O Kitzman, Heikki A Koistinen, Jie Liu, Michael Boehnke, Francis S Collins, Laura J Scott, Stephen C J Parker.

Skeletal muscle tissue underlies several polygenic metabolic traits and diseases. Identifying their genetic mechanisms requires pinpointing cell types, regulatory elements, target genes and causal variants. Here we use genetic multiplexing to generate population-scale single-nucleus chromatin accessibility (single-nucleus assay for transposase-accessible chromatin using sequencing (snATAC-seq)) and transcriptome (single-nucleus RNA sequencing (snRNA-seq)) maps across 287 frozen human skeletal muscle biopsies. We identify 13 cell types and integrate genetic variation to discover >7,000 expression quantitative trait loci (eQTLs) and >100,000 chromatin accessibility QTLs (caQTLs) across cell types, including context-specific eQTL/caQTL with significant G × C interaction. We identify nearly 2,000 eGenes colocalized with caQTL and construct causal directional maps for chromatin accessibility and gene expression. Almost 3,500 genome-wide association study (GWAS) signals across 38 relevant traits colocalize with sn-eQTL/caQTL, most in a cell-specific manner. These signals typically colocalize with caQTL and not eQTL, highlighting the importance of population-scale chromatin profiling for GWAS functional studies. The results of this study illuminate the genetic regulatory architecture of human skeletal muscle.

DOI: https://doi.org/10.1038/s41588-026-02786-6
Nat Cardiovasc Res. 2026 Oct 27.

Manipulation of ER-mitochondria interactions with mitofusin modulators reduces cardiac damage during myocardial infarction in mice.

Joshua L Axelrod, Zuzana Nichtová, Timothy Schneider, Jaehoon Lee, Ryan Pekson, Dongze Qin, Madeeha Ghazi, Vinay Kumar, Victoria Margulets, Lorrie A Kirshenbaum, Gaetano Santulli, György Csordás, John W Calvert, Richard N Kitsis.

Mitofusin (MFN) 1 and MFN2 are large outer mitochondrial membrane GTPases. Dimerization of MFNs on adjacent mitochondria mediates mitochondrial fusion. MFN2, but not MFN1, also resides at the endoplasmic reticulum (ER)/sarcoplasmic reticulum (SR) membrane, and dimerization of MFNs on ER/SR and mitochondria tethers the two organelles. Here we report that cell-permeable peptides that perturb MFN conformations regulate myocardial infarct size by impacting ER/SR-mitochondria interactions and Ca2+ transfer independently of changes in mitochondrial fusion. MFN activators increase ER/SR-mitochondria proximity, promote ER/SR to mitochondria Ca2+ transfer and exacerbate infarct size in mice, with effects dependent on MFN2, but not MFN1, and on mitochondrial calcium uniporter, which transports Ca2+ into the mitochondrial matrix. Conversely, although ER/SR-mitochondria proximity is not affected, MFN inhibitors reduce mitochondrial Ca2+ transfer and infarct size, even when their administration is delayed until reperfusion. These findings demonstrate the feasibility of acutely modulating ER/SR-mitochondria interactions and Ca2+ dynamics and suggest that pharmacological MFN inhibition may provide a new therapeutic strategy to limit cardiac damage during reperfused myocardial infarction.

DOI: https://doi.org/10.1038/s44161-026-00903-6
Biochim Biophys Acta Mol Cell Res. 2026 Oct 24. pii: S0167-4889(26)00140-0. [Epub ahead of print] 120241

Mitochondrial DNA replication and genome stability: From mechanisms to therapeutic strategies.

Maria Falkenberg, Claes M Gustafsson.

  Replication of the mitochondrial genome is essential to sustain cellular energy conversion, and defects in this process cause severe, progressive mitochondrial diseases that have long lacked curative treatment. This is now beginning to change: mechanistic insight into the replication machinery has started to translate into therapy, with the first disease-modifying treatment recently approved and others entering clinical evaluation. Here we review the molecular mechanisms of mitochondrial DNA replication, with emphasis on replication initiation, deletion formation, and replication completion, and discuss how insights into these processes are opening new therapeutic possibilities for treating mitochondrial disease.

Keywords:  DNA replication; Deletion formation; Mitochondrial disease; POLG; Treatment

DOI:  https://doi.org/10.1016/j.bbamcr.2026.120241
Adv Sci (Weinh). 2026 Oct 29. pii: e78487. [Epub ahead of print]

Lactate Drives Pathological Browning of White Adipose Tissue to Aggravate Sepsis-Associated Metabolic Disorders in a GPR81-Dependent Manner.

Chunliang Zheng, Xiaohua Li, Shuo Li, Chungen Xing, Chun Cao.

  Lactate serves as a prognostic biomarker for sepsis, yet its adipose-centered signaling pathway driving persistent metabolic disorders remains unclear. We reveal that lactate accumulation triggers browning of white adipose tissue (WAT) via GPR81 to aggravate sepsis-induced hypermetabolism, muscle wasting, and insulin resistance. Septic patients exhibit hyperlactatemia and WAT browning, with lactate concentrations correlated with fat and muscle loss. Genetically deleting UCP1 substantially attenuates LPS-induced hypermetabolism, muscle wasting, and insulin resistance, confirming WAT browning as a major mediator of sepsis-associated metabolic disorders. Lactate supplementation and pharmacological interventions using glycolysis or lactate dehydrogenase inhibitors identify lactate as the upstream pathogenic trigger. Using siRNA screening, global GPR81 knockout, and AAV9-mediated adipose-specific GPR81 knockdown, we identify GPR81 as the lactate receptor mediating UCP1 upregulation. Mechanistically, GPR81 activation induces CTRP6 and p-p38 to upregulate UCP1. AAV9-mediated overexpression of CTRP6/MKK6 in GPR81-/- mice, together with pharmacological downregulation of CTRP6 or inhibition of p-p38, supports the involvement of this pathway in WAT browning. Taken together, evidence from clinical data, gene-knockout mice, and primary adipocyte experiments demonstrates that lactate drives WAT browning in a GPR81-dependent manner to aggravate sepsis-associated metabolic disorders, identifying potential targets for therapeutic investigation in metabolic disorders unresponsive to conventional anti-infective and nutritional support treatments.

Keywords:  GPR81‐CTRP6‐p38 pathway; UCP1; lactate; metabolic disorders; sepsis; white adipose tissue browning

DOI:  https://doi.org/10.1002/advs.78487
Nature. 2026 Oct 28.

Genetic variants shape single-cell chromatin accessibility and disease risk.

Angli Xue, Jianan Fan, Oscar A Dong, Hao Lawrence Huang, Ling Chen, Peter C Allen, Eleanor Spenceley, Eszter Sagi-Zsigmond, Blake Bowen, Albert Henry, Anna S E Cuomo, Hope A Tanudisastro, Zhen Qiao, Elizabeth Dorans, Eyal Ben-David, Kyle Kai-How Farh, Linfeng Hu, Yijia Christiana Liu, Drew R Neavin, Arthur S Lee, Anne Senabouth, Caitlin Bartie, Rachael A McCloy, Venessa Chin, Wei Zhou, Alkes L Price, Katrina M de Lange, Gemma A Figtree, Alex W Hewitt, Daniel G MacArthur, Joseph E Powell.

Understanding how genetic variation shapes gene regulation at single-cell resolution is crucial for elucidating complex disease mechanisms1, but has been limited by the lack of large-scale single-cell multi-omics data2-4. Here we present single-cell assay for transposase-accessible chromatin with sequencing of 3.5 million peripheral blood mononuclear cells from 1,042 donors with matched whole-genome sequencing. Across 28 immune cell types, we tested 440,996 chromatin accessibility peaks and identified 243,225 chromatin accessibility quantitative trait loci (caQTLs) at 100,483 peaks, 60% of them cell-type specific. Rare variant analysis identified 38,161 associated peaks, with predicted transcription factor-binding disruption implicated at individual loci. Colocalization with expression QTLs (eQTLs) from single-cell RNA sequencing data (5.4 million peripheral blood mononuclear cells)5 defined 28,834 candidate cis-regulatory elements. Across genome-wide association studies for 16 diseases and 44 blood traits, caQTLs colocalized 4.5-22.6% more signals than eQTLs alone. Cell-type-specific and tissue-specific context, distal effects and multi-causal-variant models raised genome-wide association study-eQTL concordance from approximately 16% to approximately 65%. Cell state further modulates genetic effects, with 27% of over 200,000 caQTL-cell-state interactions lacking a main effect. At the inflammatory bowel disease risk gene ADCY7, accessibility effects varied with genotype and G protein-mediated pathway activity in CD4+ T cells. A graph neural network trained on both eQTL and caQTL layers inferred peak-gene links in unpaired multiome data with up to 17.2% higher accuracy than QTL-agnostic data, uncovering 128 additional transcription factor-target pairs (22% increase). Together, these results show that genetic variants shape chromatin accessibility in a cell-type-specific and cell-state-specific manner, influencing immune function and disease risk.

DOI: https://doi.org/10.1038/s41586-026-11173-4
bioRxiv. 2026 Oct 09. pii: 2026.10.08.756856. [Epub ahead of print]

Systematic mapping of enhancers, silencers, and topological elements with prime editing deletion screens.

Xiangmeng Shawn Cai, Michael T Montgomery, Masahiro Nagano, Ashna Nisal, Zhengxi Gu, Ziwei Chen, Kamal Obbad, Ruchir Rastogi, Yingxuan Tan, Tony Zeng, Maya U Sheth, Coco Xia, Shannon Chiang, Anshul Kundaje, Anders S Hansen, Lacramioara Bintu, Jesse M Engreitz.

Noncoding regulatory elements in the human genome can control gene expression through distinct mechanisms, including acting as enhancers, silencers, or topological elements. However, we lack tools to identify all such classes systematically and quantify their effects on gene expression in an endogenous genomic context. Here we develop Swap-seq, a method that combines pooled twin prime editing with flow-sorting to delete hundreds of endogenous regulatory sequences and measure their quantitative effects on the expression of a nearby gene. We apply Swap-seq to dissect the regulatory elements that control PPIF expression in THP-1 monocytes. We quantify the effects of distal and intronic enhancers, characterize CTCF insulators, and discover a silencer that regulates distal genes through histone deacetylase (HDAC)-mediated repression of neighboring enhancers. Hundreds of other genomic elements share its chromatin signatures and transcription factor binding sites, suggesting that this silencer represents a broader class of repressive elements. We leverage Swap-seq data to benchmark sequence-to-function models and show that they often capture the local activity of regulatory elements but fail to link them to distal target genes. Swap-seq thus provides a generalizable tool to discover regulatory elements across mechanistic classes, characterize their effects on gene expression, and generate large-scale datasets for evaluating sequence-to-function models.

DOI: https://doi.org/10.64898/2026.10.08.756856
Nucleic Acids Res. 2026 Oct 31. pii: gkag1086. [Epub ahead of print]

MetabDB: an integrated resource for human metabolic measures, disease associations, and genetic evidence.

Dandan Huang, Xinxin Shi, Sifan Cui, Qinyi Xu.

Population-scale metabolomics studies have linked metabolic measures to diseases, quantitative traits, and genetic variation, but the results are scattered across assay platforms, phenotype definitions, and analytical formats. MetabDB integrates 16 public studies spanning nuclear magnetic resonance, mass spectrometry, and lipidomics. The current release contains 2663 metabolic measures, 3524 diseases and outcomes, 3382 other genome-wide association traits, and 2025 molecular quantitative trait locus (QTL) targets. MetabDB links genomic variants, genes and proteins, metabolic measures, and diseases or traits through variant/QTL associations, fine-mapping, rare-variant or burden analyses, colocalization, Mendelian randomization, and population associations. Metabolic measures areretained in their source-reported forms, including compounds, lipid species, lipoprotein measures, ratios, percentages, and derived traits. Gene- and protein-level evidence can be examined alongside genomic signals and related disease or trait evidence for the same metabolic measure. Source information and reported analytical details are retained, including the source study, original variable or phenotype definition, assay, unit, exposure scale, analytical model, and statistics where available. Search, browse, and colocalization pages, together with gene evidence breadth and disease-association profiles, provide access to these records. MetabDB is freely available at http://www.mulinlab.org/metabdb/.

DOI: https://doi.org/10.1093/nar/gkag1086
Signal Transduct Target Ther. 2026 Oct 27. pii: 471. [Epub ahead of print]11(1):

The AMPK signaling pathway in cell metabolism and human diseases.

Zhengkui Zhang, Yuanzhuo Gu, HongChao He, Shilei Qiao, Yifan Shao, Xianming Long, Jun Huang, Long Zhang, Fangfang Zhou.

Adenosine 5'-monophosphate-activated protein kinase (AMPK), a highly conserved energy-sensing kinase, plays a central role in maintaining cellular metabolic homeostasis, such as glucose/lipid metabolism, mitochondrial biogenesis, and autophagy, to counteract energetic stress. Beyond the canonical adenylate-dependent activation of AMPK by sensing the ATP:AMP/ADP ratio, emerging evidence reveals noncanonical activation mechanisms. Proper AMPK signaling is essential for physiological functions, whereas its dysregulation underlies various pathologies, including metabolic diseases, immune disorders, and cancer. This review systematically recapitulates the historical background and landmark discoveries of the AMPK field, including the discovery of AMPK, the structure of AMPK complex, upstream regulators and downstream substrates, and the transcriptional/posttranscriptional and posttranslational regulatory mechanisms. Furthermore, we delineate its roles in maintaining metabolic equilibrium, mitochondrial integrity, and immune competence across organ systems and highlight how dysregulated AMPK activity contributes to pathological diseases, encompassing alterations in its expression levels, intrinsic kinase activity, subcellular localization or upstream regulatory signaling cascades. Specifically, we focus on knock-in or knockout mouse models utilized to study AMPK-associated human diseases and the translational potential of AMPK-targeting agonists or antagonists across diverse pathological conditions. A deep understanding of the multidimensional regulatory network of AMPK and mechanistic insights with therapeutic innovations that we provide with this review will help address the challenges of complex metabolic diseases.

DOI: https://doi.org/10.1038/s41392-026-02790-6
Nat Commun. 2026 09 25. pii: 11146. [Epub ahead of print]17(1):

An epigenetic aging-informed dietary pattern is associated with a spectrum of aging-related health outcomes.

Sirui Lai, Jie Yu, Li Zhang, Min Wu, Guoping Peng, Geng Zong, Hao Ma, Changzheng Yuan, Benyan Luo, Hui Chen.

Diet is associated with biological aging, yet few existing dietary indices have been developed specifically to target biological aging. We develop a data-driven, food-based Empirical Dietary Index for Slower Epigenetic Aging (EDISEA) to identify dietary features predictive of lower GrimAge2 acceleration. Higher EDISEA is associated with 4.17 years slower epigenetic aging in the derivation sample of 1,711 participants (P-value < 0.001) and 3.77 years slower aging in an independent sample of 2,311 participants. Higher EDISEA is consistently associated with lower all-cause mortality (pooled hazard ratio = 0.80, 95% CI 0.76, 0.85) in two US cohorts, and with lower risks of aging-related diseases, functional limitations, and multimorbidity across US and UK aging cohorts. Outcome-wide analyses in a large UK population-based cohort further show broad health associations, supported by molecular and neuroimaging signatures of more favourable vascular, inflammatory, metabolic, and brain structural profiles. EDISEA may provide an epigenetic aging-informed framework for studying dietary strategies relevant to healthy aging.

DOI: https://doi.org/10.1038/s41467-026-77790-9
Cell Death Dis. 2026 Aug 01. pii: 922. [Epub ahead of print]17(1):

Inhibition of lactate-histone lactylation mediated cardiomyocyte-fibroblast communication mitigates cardiac fibrosis in cardiomyopathy models with Hippo pathway activation.

Li-Ye Jia, Xia-Xia Hai, Zhi-Qiang Wu, Jing-Jing Li, Yi-Yi Yang, Meng-Chen Hou, Lin-Hong Wu, Meng-Zhuan Han, Yi Zhang, Yungang Xu, Jie Deng, Bao-Chang Lai, Junichi Sadoshima, Xiu-Ling Deng, Zheng-Da Pang, Xiao-Jun Du, Gang She.

Metabolic remodeling is a fundamental mechanism that underlies cardiomyopathy and heart failure. Preclinical and clinical studies in diverse types of heart disease have provided evidence for the activation of the myocardial Hippo pathway and that cardiomyocyte-specific Hippo pathway activation or YAP-TEAD1 inactivation drives cardiomyocyte mitochondrial damage, metabolic abnormalities and fibrosis. Here we studied whether intervention of myocardial lactate metabolism have therapeutic effect on cardiac fibrosis in cardiomyopathy models. In a Hippo pathway-activated mouse model (Mst1-cTG), single-nucleus RNA-sequencing (snRNA-seq) revealed activated fibroblasts while cardiomyocytes displayed downregulation of gene sets of mitochondrial metabolism and augmented HIF-1 signaling. Seahorse assay in isolated cardiomyocytes from adult TG mice showed impaired oxidative respiratory capacity together with enhanced glycolysis and lactate production. In TG mouse myocardium, fibroblast histone H3 lysine 18 lactylation (H3K18la), regulated by p300, was elevated starting from young age. By CUT&Tag, H3K18la was found to be enriched in promoter regions of numerous fibrotic genes with enhanced transcription. Treatment of TG mice with inhibitors to suppress either glycolysis (PX-478 as HIF-1α inhibitor) or lactate production (FX-11 as LDHA inhibitor) reduced both myocardial lactate content and H3K18la level, and ameliorated cardiac fibrosis and dysfunction. Similar efficacy was achieved in vitro or in vivo by fibroblast p300 knockdown using siRNA or AAV9. Treatment with FX-11 was similarly effective in inhibiting histone lactylation and fibrosis in mice subjected to chronic ischemia-reperfusion. Finally, we integrated our snRNA-seq and CUT&Tag studies to identify RUNX2 as a crucial transcription factor that promotes fibrotic gene expression in concert with H3K18la levels. Treatment with RUNX2 inhibitor CADD522 in TG mice improved heart dysfunction and fibrosis. In the setting of myocardial Hippo pathway activation, inhibiting the lactate-histone lactylation-RUNX2 axis effectively attenuated cardiac fibrosis. Myocardial Hippo pathway activation promotes the production and release of lactate that acts in a paracrine signaling fashion to activate fibroblasts through upregulation of fibroblast H3K18la and enhancing the enrichment of RUNX2 to the promoter regions of fibrotic genes with enhanced gene transcription, ultimately leading to cardiac fibrosis. Suppressing the lactate-histone lactylation-RUNX2 axis is protective against cardiac fibrosis.

DOI: https://doi.org/10.1038/s41419-026-09137-7
Nature. 2026 Oct 28.

Rare and common genetic variants shape single-cell immune gene expression.

Anna S E Cuomo, Eleanor Spenceley, Hope A Tanudisastro, Blake Bowen, Albert Henry, Hao Lawrence Huang, Angli Xue, Wei Zhou, Matthew J Welland, Samantha J Bryen, Oscar A Dong, Arthur S Lee, Jeffrey M Pullin, Kristof Wing, Owen Tang, Michael P Gray, Michael Franklin, Michael Harper, Michael Silk, Katalina Bobowik, Alexander Stuckey, John Marshall, Vivian Bakiris, Caitlin Uren, Rachael A McCloy, Bindu Swapna Madala, Amy Miniter, Caitlin Bartie, Drew R Neavin, Zhen Qiao, Eyal Ben-David, Ling Chen, Kyle Kai-How Farh, Stuart M Grieve, Tung Nguyen, Chris Wallace, Jennifer Piscionere, Owen M Siggs, Hannah Nicholas, Katrina M de Lange, Alex W Hewitt, Gemma A Figtree, Daniel G MacArthur, Joseph E Powell.

Understanding the genetic basis of gene expression can shed light on the regulatory mechanisms underlying complex traits and diseases1,2. Single-cell-resolved measures of RNA levels and single-cell expression quantitative trait loci have revealed genetic regulation that drives cell states and types across diverse tissues3. Here we describe phase 1 of TenK10K, which leverages single-cell RNA sequencing data from more than 5 million cells across 28 immune cell types, along with matched whole-genome sequencing data from 1,925 individuals. This provides power to detect associations for rare and low-frequency genetic variants that have largely been uncharacterized in their impact on cell-specific gene expression. We map the effects of both common and rare variants in a cell-type-specific manner using a recent method that increases power by modelling single cells directly rather than aggregated 'pseudobulk' counts. We identify putative common regulatory variants for 83% of all 21,404 genes tested and cumulative rare-variant signals for 47% of those genes. We explore how genetic effects vary across cell types and states, develop a framework to determine the degree of single-cell expression quantitative trait loci cell-type specificity and show that about half of the effects are observed only in one or a few cell types. By integrating our results with functional annotations and disease information, we further characterize the likely molecular modes of action for many disease-variant associations. Finally, we explore the effects that genetic variants have on gene expression across continuous cell states, and effects that vary cell-state abundance directly.

DOI: https://doi.org/10.1038/s41586-026-10721-2