bims-obesme 2026-03-15 papers

bims-obesme

Biomed News

on Obesity metabolism

Issue of 2026–03–15
twelve papers selected by
Xiong Weng, University of Edinburgh

Immune cells regulate circulating adipocyte extracellular vesicle levels in response to metabolic shifts.
HIF1α reinforces PPARγ-dependent metabolic rechanneling to support lipid accumulation in adipocytes.
Defining the vascular niche of human adipose tissue across metabolic states.
Longitudinal changes in epigenetic clocks predict survival in the InCHIANTI cohort.
Vitamin C inhibits ACSL4 to alleviate ferro-aging in primates.
Tissue-specific regulation of PNPLA3 promotes lipid remodeling in response to dietary and environmental challenges: Tissue-specific PNPLA3 lipid remodeling.
Histone modification clocks for robust cross-species biological age prediction and elucidating senescence regulation.
Plasma GDF15 increases during hyperinsulinemic hypoglycemia in humans with post-bariatric hypoglycemia and after insulin exposure in mice.
Dnmt3a-dependent de novo DNA methylation enforces lineage commitment and preserves functionality of memory Th1 and Tfh cells.
Butyrate extends health and lifespan in mice with mitochondrial deficiency.
Targeting mitochondrial metabolism with combined metabolic activators.
Acetylation-dependent nuclear translocation of EXOC4 regulates KU70 methylation to facilitate non-homologous end joining.

Cell Metab. 2026 Mar 10. pii: S1550-4131(26)00051-3. [Epub ahead of print]

Immune cells regulate circulating adipocyte extracellular vesicle levels in response to metabolic shifts.

Snigdha Tiash, Saket Awadhesbhai Patel, Marjori Russo, Anusha Suresh, Bo Pang, Yun-Ling Pai, Wentong Jia, Rachael L Field, Terri Pietka, Nada A Abumrad, Gordon I Smith, Dmitri Samovski, Samuel Klein, Jonathan R Brestoff, Clair Crewe.

  Extracellular vesicles (EVs) are now recognized as potent mediators of inter-organ signaling and are implicated in the pathogenesis of obesity and associated comorbidities. Despite a recent surge in functional information about EVs, we still lack a basic understanding of how endogenous EV levels are controlled to regulate inter-organ signaling. New flow cytometry technologies have allowed us to study the regulation of circulating endogenous EVs from metabolically relevant cell types such as adipocytes (adipocyte-derived EVs [adipoEVs]). We provide evidence for a paradigm of EV regulation in which tissue-resident immune cells, predominantly macrophages, clear EVs released by local tissue cells or those entering the tissue from circulation, an activity that determines circulating EV levels. In obesity, EV uptake by adipose tissue immune cells is reduced, leading to increased circulating adipoEVs and reduced adipoEV clearance rates. This work shows that tissue immune cells gate tissue EV entry into the circulation, making them key regulators of inter-organ EV signaling.

Keywords:  adipocyte; exosomes; extracellular vesicles; insulin resistance; inter-organ signaling; macrophage; mitochondria; obesity; spectral flow cytometry; type 2 diabetes

DOI:  https://doi.org/10.1016/j.cmet.2026.02.008
Front Mol Med. 2026 ;6 1716464

HIF1α reinforces PPARγ-dependent metabolic rechanneling to support lipid accumulation in adipocytes.

Chaonan Zhu, Meiqian Wu, Minh Duc Pham, Yue Wang, Arka Provo Das, Yijie Mao, Peter Mirtschink, Ting Yuan, Jaya Krishnan.

   Introduction: Adipose tissue hypoxia is a hallmark of obesity and partly contributes to metabolic dysfunction through effects on differentiated adipocytes. Although hypoxia-inducible factor 1α (HIF1α) is a key transcriptional mediator of hypoxic responses, its state-dependent metabolic role remains incompletely defined in mature adipocytes. Herein, we investigate how HIF1α regulates lipid metabolism in differentiated adipocytes under nutrient excess conditions.
Methods: An adipocyte-specific Hif1α knockout mouse model was subjected to high-fat diet feeding in vivo. Adipose mass, adipocyte size, glucose tolerance, and insulin sensitivity were assessed. Metabolic and enzymatic analyses focused on lipid anabolic pathways, including glycolysis-linked glycerolipid biosynthesis and PPARγ-dependent programs.
Results: Adipocyte-specific deletion of Hif1α attenuated adipocyte hypertrophy, resulting in reduced adipose mass as well as improved systemic glucose tolerance and insulin sensitivity during high-fat diet feeding. Mechanistically, HIF1α reinforced PPARγ-dependent lipid anabolic programs by coordinating glycolytic flux with glycerolipid biosynthesis to promote the rechanneling of glucose-derived intermediates into triacylglyceride synthesis.
Discussion: Together, these findings provide metabolic and enzymatic validations of a late-stage, state-dependent HIF1α-PPARγ lipid storage program and implicate the glycerol-3-phosphate dehydrogenase 1 (GPD1)-glycerol-3-phosphate acyltransferase (GPAT) axis as a key molecular executor of hypertrophic lipid accumulation in differentiated adipocytes.

Keywords:  HIF1α; adipose tissue; high-fat diet; metabolism; obesity

DOI:  https://doi.org/10.3389/fmmed.2026.1716464
Nat Metab. 2026 Mar 12.

Defining the vascular niche of human adipose tissue across metabolic states.

Ibrahim AlZaim, Mohamed N Hassan, Maja Schröter, Luca Mannino, Katarina Dragicevic, Marie Balle Sjogaard, Joseph Festa, Lolita Dokshokova, Sophie Weinbrenner, Blanca Tardajos Ayllon, Bettina Hansen, Rikke Kongsgaard Rasmussen, Julie N Christensen, Olivia Wagman, Ruby Schipper, Min Cai, Wouter Dheedene, Anja Bille Bohn, Jean Farup, Lin Lin, Samuele Soraggi, Anna Dalsgaard Thorsen, Amanda Bæk, Henrik Holm Thomsen, Maximilian von Heesen, Lena-Christin Conradi, Paul Evans, Carolina E Hagberg, Joerg Heeren, Margo Emont, Evan D Rosen, Aernout Luttun, Anders Etzerodt, Lucas Massier, Mikael Rydén, Niklas Mejhert, Matthias Blüher, Konstantin Khodosevich, Robert A Fenton, Bilal N Sheikh, Niels Jessen, Laura P M H de Rooij, Joanna Kalucka.

Adipose tissue homeostasis depends on an intact vascular network that ensures adequate nutrient delivery and immune regulation. In obesity, vascular dysfunction, particularly within endothelial cells (ECs), contributes to inflammation and metabolic disease progression, yet the cellular organization of the human adipose vasculature remains poorly defined. Here we show, using single-cell RNA sequencing of nearly 70,000 vascular cells from human subcutaneous adipose tissue of 65 individuals, that the adipose vasculature is highly heterogeneous and consists of seven canonical EC subtypes. In addition, we identify a distinct population of ECs that display mixed endothelial, mesenchymal, adipocytic and immune transcriptional features. Computational analyses and whole-mount imaging support their presence and suggest that they emerge through endothelial-to-mesenchymal transition. Comparative analyses further reveal inflammatory and fibrotic vascular signatures in obesity and type 2 diabetes. Together, this atlas delineates the cellular complexity of the human adipose vasculature and highlights its contribution to metabolic disease.

DOI: https://doi.org/10.1038/s42255-026-01475-2
Nat Aging. 2026 Mar 13.

Longitudinal changes in epigenetic clocks predict survival in the InCHIANTI cohort.

Pei-Lun Kuo, Ann Zenobia Moore, Toshiko Tanaka, Daniel W Belsky, Ake Tzu-Hui Lu, Steve Horvath, Stefania Bandinelli, Luigi Ferrucci.

Epigenetic clocks derived from DNA methylation patterns are among the most promising biomarkers of biological aging1-7, as they capture molecular signatures that predict morbidity and mortality beyond chronological age. Although cross-sectional assessments of epigenetic age have been linked consistently to health outcomes and lifespan, it remains unclear whether the rate of change in these clocks over time provides additional insight into aging trajectories. In this longitudinal study of 699 adults from the InCHIANTI cohort followed for up to 24 years, we evaluated whether temporal acceleration of several epigenetic clocks-including first-, second- and third-generation epigenetic clocks-was associated with mortality. We found that faster increases in several clocks were linked robustly to higher risk of death, independent of baseline epigenetic age and other confounders. These findings suggest that dynamic changes in epigenetic aging reflect evolving health status and may serve as sensitive indicators for interventions aimed at extending healthspan and longevity.

DOI: https://doi.org/10.1038/s43587-026-01066-6
Cell Metab. 2026 Mar 11. pii: S1550-4131(26)00053-7. [Epub ahead of print]

Vitamin C inhibits ACSL4 to alleviate ferro-aging in primates.

Lixiao Liu, Zikai Zheng, Wanbang You, Peng Yang, Yifan Wen, Yicheng Qiao, Shuai Ma, Hui Zhang, Shuo Zhang, Gang Xu, Chencan Ma, Ao Tian, Mengmeng Jiang, Tongtong Zhang, Lingling Geng, Jingyi Li, Xiaoyan Sun, Feibo Wang, Muzhao Xiong, Yuanhan Yang, Xiaoyong Lu, Xiaoyu Jiang, Xueda Dong, Zhiyi Zhang, Ying Huang, Baohu Zhang, Qin Qiao, Shuhui Sun, Yanling Fan, Yusheng Cai, Kaowen Yan, Yiyuan Zhang, Ying Jing, Yaobin Jing, Qiaoran Wang, Jinghui Lei, Ansheng Tan, Zichu Han, Pradeep Reddy, Amin Haghani, Concepcion Rodriguez Esteban, Feng Zhang, Zhili Liu, Ning Liu, Si Wang, Steve Horvath, Jiayin Yang, Juan Carlos Izpisua Belmonte, Weiqi Zhang, Jing Qu, Guang-Hui Liu.

  Aging is associated with oxidative stress, but specific druggable pathways remain elusive. Here, we define a conserved iron-lipid axis driving primate aging, termed "ferro-aging." Multi-tissue profiling in humans and non-human primates reveals age-progressive iron accumulation, fueling chronic lipid peroxidation orchestrated by acyl-coenzyme A (CoA) synthetase long-chain family member 4 (ACSL4). Distinct from acute ferroptosis, this ACSL4-mediated process promotes cellular senescence and systemic functional decline. The therapeutic inhibition of hepatic ACSL4 via gene editing alleviates aging phenotypes in mice. Through functional screening and target engagement studies, we identify vitamin C (VC) as a direct inhibitor of ACSL4. Long-term VC administration in aged monkeys for over 40 months potently reduces ferro-aging signatures across tissues, attenuates multi-organ pathology, and improves neurological and metabolic functions. Multi-omic aging clocks indicate the VC-mediated reversal of biological age. Our work establishes ferro-aging as a core, targetable mechanism of primate aging and positions VC as a translatable geroprotective strategy through ACSL4 inhibition.

Keywords:  ACSL4; NRF2; aging; ferro-aging; iron; primate; senescence; vitamin C

DOI:  https://doi.org/10.1016/j.cmet.2026.02.010
J Hepatol. 2026 Mar 07. pii: S0168-8278(26)00124-8. [Epub ahead of print]

Tissue-specific regulation of PNPLA3 promotes lipid remodeling in response to dietary and environmental challenges: Tissue-specific PNPLA3 lipid remodeling.

Panyun Wu, Yang Wang, Jonathan C Cohen, Helen H Hobbs.

   BACKGROUND & AIMS: PNPLA3(I148M) is the strongest genetic risk factor for steatotic liver disease (SLD), but its functional role and tissue-specific regulation remain unclear. Pnpla3 mRNA levels are significantly higher in mouse adipose tissue than liver, yet its role in adipose tissue is not known. Here, we characterize the molecular mechanisms underlying tissue-specific differences in PNPLA3 expression in mice to clarify its functional role and link to SLD risk.
METHODS: Pnpla3 mRNA and PNPLA3 protein levels were quantified in liver and adipose depots of fasted and refed mice at 30°C and 6°C. Signaling pathways regulating PNPLA3 expression in adipocytes were examined using adrenergic agonists and pathway-specific modulators. Translation and proteasomal inhibitors were used during adrenergic stimulation to investigate the discordance between Pnpla3 mRNA and protein levels. Relationship between PNPLA3 levels and triglyceride (TG) fatty acid composition was also assessed.
RESULTS: At thermoneutrality, feeding strongly increased PNPLA3 levels in liver but it remained undetectable in adipose tissue. Conversely, cold exposure or β3-adrenergic stimulation had no effect on hepatic PNPLA3, but increased PNPLA3 >19-fold in brown adipose tissue (BAT), despite causing a >75% reduction in Pnpla3 mRNA, indicating robust post-translational regulation. In BAT, adrenergic signaling via cAMP/PKA and PI3K/AKT elevated PNPLA3 by reducing proteasomal degradation. PNPLA3 expression correlated with depletion of TG-long-chain polyunsaturated fatty acids (TG-LCPUFAs) in both liver and BAT, consistent with a role in lipid remodeling.
CONCLUSIONS: These findings reveal striking tissue- and context-specific regulation of PNPLA3, but a conserved association between its expression and TG-LCPUFAs levels, suggesting that PNPLA3 modulates lipid remodeling in response to metabolic stress and that disrupting this function may contribute to SLD susceptibility.
IMPACT AND IMPLICATIONS: Despite being the strongest genetic risk factor for SLD, PNPLA3's physiological role remains unclear. Using mouse models, this study reveals that PNPLA3 is regulated in a tissue-specific manner in response to feeding and cold exposure, thereby promoting remodeling of cellular lipids to adapt to dietary and environmental challenges. The localization of PNPLA3 action and its tissue-specific regulation are directly relevant to hepatologists and metabolic researchers aiming to understand its influence on intracellular lipid composition and its effects on disease susceptibility. Moreover, modulation of PNPLA3 turnover-and its impact on LCPUFAs remodeling-emerges as a potential therapeutic strategy for regulating lipid homeostasis in SLD.

Keywords:  adipose tissue; cold exposure; lipid droplets; lipolysis

DOI:  https://doi.org/10.1016/j.jhep.2026.02.029
Proc Natl Acad Sci U S A. 2026 Mar 17. 123(11): e2533687123

Histone modification clocks for robust cross-species biological age prediction and elucidating senescence regulation.

Zhixin Niu, Chang Liu, Yurong Fan, Lei Gu.

  Histone modifications represent an untapped resource for biological age prediction that overcomes limitations of traditional DNA methylation-based epigenetic clocks. Here, we developed and validated histone modification-based epigenetic clocks by systematically analyzing publicly available ChIP-seq datasets spanning six tissue types and six histone marks. We identified age-associated loci and constructed 36 tissue-specific epigenetic clocks that demonstrated strong resilience to technical and biological noise, with performance comparable to established DNA methylation clocks. Our models successfully detected biological age acceleration in leukemia samples and captured age reversal following therapeutic interventions. Importantly, we found that many aging-associated loci follow nonlinear trajectories with peak modification levels at midlife, revealing previously unrecognized dynamics in epigenetic aging. We observed age-related fragmentation of super enhancer regions, suggesting progressive chromatin disorganization during aging. Functional validation of a model-selected H3K27ac peak near IGF2BP3 confirmed its causal role in cellular senescence through regulation of TRA2A expression. Extending beyond mammals, we demonstrated the applicability of histone-based clocks in Drosophila melanogaster, a species lacking DNA methylation, highlighting the evolutionary conservation and broader utility of histone modifications as aging biomarkers. Our findings establish histone modifications as accurate, biologically meaningful, and robust indicators of biological age with potential applications in aging research, disease monitoring, and therapeutic development across diverse species.

Keywords:  aging; epigenetics; histone modification

DOI:  https://doi.org/10.1073/pnas.2533687123
Cell Rep Med. 2026 Mar 09. pii: S2666-3791(26)00073-X. [Epub ahead of print] 102656

Plasma GDF15 increases during hyperinsulinemic hypoglycemia in humans with post-bariatric hypoglycemia and after insulin exposure in mice.

Rafael Ferraz-Bannitz, Lei Pei, Hanna Wang, Berkcan Ozturk, Pilar Casanova Querol, Alessandra Gonçalves da Cruz, Tyler M Cook, Hamayle Saeed, Leila Osterwalder, Lindsay Poulos, Hany Saifeldin, Cameron Cummings, Maryam Farahmandsadr, Alessandra Amore, Amanda Sheehan, Donald C Simonson, Darleen A Sandoval, Mary-Elizabeth Patti.

  Post-bariatric hypoglycemia (PBH), characterized by excessive postprandial incretin and insulin secretion, is a common complication of bariatric surgery. Here, we investigate the relationship between PBH and growth differentiation factor 15 (GDF15) in individuals with PBH after Roux-en-Y gastric bypass (RYGB), post-RYGB individuals who remain asymptomatic (Asx), and individuals with overweight/obesity but without history of surgery (Ow/Ob). Fasting plasma GDF15 is higher in PBH vs. Ow/Ob and further increases postprandially, coinciding with hypoglycemia symptoms. During a hyperinsulinemic hypoglycemic clamp, GDF15 progressively increases in PBH and correlates with hypoglycemia survey symptoms, including weakness, difficulty concentrating, feeling cold, and tingling lips. In mice, insulin-induced hypoglycemia also results in elevated GDF15 levels, and exogenous recombinant GDF15 (rGDF15) reduces food intake in response to hypoglycemia. Our data suggest that GDF15 modulates the counterregulatory response to hypoglycemia in both PBH individuals and mice and that elevated GDF15 levels contribute to hypoglycemia-related postprandial symptoms. This study was registered at ClinicalTrials.gov (NCT04428866).

Keywords:  GDF15; counterregulatory response; hypoglycemia; hypoglycemia symptoms; post-bariatric hypoglycemia

DOI:  https://doi.org/10.1016/j.xcrm.2026.102656
Cell Rep. 2026 Mar 10. pii: S2211-1247(26)00140-3. [Epub ahead of print]45(3): 117062

Dnmt3a-dependent de novo DNA methylation enforces lineage commitment and preserves functionality of memory Th1 and Tfh cells.

Bryant Perkins, Camille L Novis, Andrew Baessler, Linda M Sircy, Monyca M Thomas, Malia Harrison-Chau, Andrew W Richens, Bryce Fuchs, Nguyen X Nguyen, Kaitlyn Flint, Brittany S Winter, Katherine E Varley, J Scott Hale.

  Following acute viral infection, naive CD4+ T cells differentiate into T follicular helper (Tfh) and T helper 1 (Th1) cells that generate long-lived memory. However, it is unclear how memory Tfh and Th1 cells maintain their lineage commitment. We demonstrate that Tfh and Th1 lineages acquire distinct Dnmt3a-dependent de novo DNA methylation programs that are preserved into memory. Dnmt3a deletion impairs memory Th1 and Tfh cell lineage commitment and functionality, resulting in aberrant Runx1 upregulation that represses germinal center Tfh cell differentiation. In contrast, transient pharmacological DNA methyltransferase inhibition during priming impairs repression of Tfh-associated genes while properly silencing Runx1, resulting in enhanced primary and secondary germinal center Tfh cell responses. Together, these findings demonstrate that Dnmt3a-mediated DNA methylation programming is required to enforce T helper lineage commitment and preserve lineage-specific functions during the recall response to infection and reveal strategies to improve long-lived adaptive immunity against infectious diseases.

Keywords:  CP: Immunology; DNA methylation; Dnmt3a; Runx1; Tfh; Th1; epigenetics; germinal center; memory

DOI:  https://doi.org/10.1016/j.celrep.2026.117062
Nat Commun. 2026 Mar 13.

Butyrate extends health and lifespan in mice with mitochondrial deficiency.

Enrique Gabandé-Rodríguez, Manuel M Gómez de Las Heras, Pablo Ramírez-Ruiz de Erenchun, Carolina Simó, Virginia García-Cañas, Naohiro Inohara, Inés Berenguer-López, Violeta Enríquez-Zarralanga, Álvaro Fernández-Almeida, Jorge Oller, Gonzalo Soto-Heredero, Elisa Carrasco, Cristina Vázquez-Muñoz, Sandra Delgado-Pulido, José Ignacio Escrig-Larena, Isaac Francos-Quijorna, Raquel Justo-Méndez, Juan Francisco Aranda, Joanna Poulton, Ana Victoria Lechuga-Vieco, José Antonio Enríquez, Gabriel Núñez, María Mittelbrunn.

Mitochondrial diseases progressively lead to multisystemic failure with treatment options remaining extremely limited. Here, to investigate strategies that alleviate mitochondrial dysfunction, we first generate a ubiquitous and tamoxifen-inducible knockout mouse model of mitochondrial transcription factor A (TFAM), a nuclear-encoded protein involved in mitochondrial DNA (mtDNA) maintenance - Tfamfl/flUbcCre-ERT2 (iTfamKO) mice. Systemic TFAM deficiency triggers mitochondrial decline in a myriad of tissues in adult mice. Consequently, iTfamKO mice manifest multiorgan dysfunction including lipodystrophy, sarcopenia, metabolic alterations, kidney failure, neurodegeneration, and locomotor dysregulation, which result in the premature death of these mice. Interestingly, iTfamKO mice display intestinal barrier disruption and gut dysbiosis, with diminished levels of microbiota-derived short-chain fatty acids (SCFAs), such as butyrate. Mice with a deficient proof-reading version of the mtDNA polymerase gamma (mtDNA-mutator mice) phenocopy the dysfunction of the intestinal barrier and bacterial dysbiosis with reduced levels of butyrate, suggesting that different mouse models of mitochondrial dysfunction share insufficient generation of butyrate. Transfer of microbiota from healthy control mice or administration of tributyrin, a butyrate precursor, delay multiple signs of multimorbidity, extending lifespan in iTfamKO mice. Mechanistically, butyrate supplementation recovers epigenetic histone acylation marks that are lost in the intestine of Tfam deficient mice. Overall, our findings highlight the relevance of preserving host-microbiota symbiosis in disorders related to mitochondrial dysfunction.

DOI: https://doi.org/10.1038/s41467-026-70547-4
Trends Endocrinol Metab. 2026 Mar 07. pii: S1043-2760(26)00034-2. [Epub ahead of print]

Targeting mitochondrial metabolism with combined metabolic activators.

Hong Yang, Xiangtai Kong, Xinmeng Liao, Hasan Turkez, Jan Boren, Mathias Uhlen, Ozlem Altay, Adil Mardinoglu.

  Mitochondria play a central role in energy metabolism, redox balance, and cellular homeostasis, and their dysfunction has been implicated in the pathogenesis of complex human diseases. Advances in systems biology and omics technologies have elucidated the mechanisms underlying these conditions, including metabolic dysfunction, mitochondrial impairment, inflammation, and redox imbalance. Preclinical and early clinical studies of combined metabolic activators (CMA), a formulation of bioactive metabolites, have demonstrated improvements in mitochondrial function and systemic metabolic profiles across multiple diseases. In this review, we provide a comprehensive overview of the mechanistic rationale for CMA, summarize evidence from preclinical models and clinical studies investigating CMA and its components, and evaluate its translational potential and challenges as a mitochondrial-targeted therapeutic strategy for complex human diseases.

Keywords:  NAD(+); combined metabolic activators; glutathione; l-carnitine tartrate; metabolic diseases; mitochondrial dysfunction; serine

DOI:  https://doi.org/10.1016/j.tem.2026.01.018
Cell Death Differ. 2026 Mar 14.

Acetylation-dependent nuclear translocation of EXOC4 regulates KU70 methylation to facilitate non-homologous end joining.

Haojie Li, Haoyu Sun, Xu Yang, Wenchao Jiang, Xinyou Liu, Bosen Li, Chenyu Tian, Junjie Zhao, Yuanyuan Ruan, Jie Sun, Xuefei Wang.

Chemoradiotherapy resistance remains a major obstacle in gastric cancer treatment, primarily due to enhanced DNA repair mechanisms that allow tumor cells to overcome therapeutic damage. Here, we demonstrate that nuclear-localized Exocyst Complex Component 4 (EXOC4) promotes chemoradiotherapy resistance in gastric cancer by enhancing non-homologous end joining-mediated DNA repair. Specifically, p300-mediated acetylation of EXOC4 at lysine 433 induces its nuclear translocation. In the nucleus, EXOC4 facilitates the interaction between PRMT5 and KU70, inducing PRMT5-catalyzed methylation of KU70 at arginine 318. This modification increases the DNA-binding affinity of the KU complex, thereby accelerating double-strand break repair. A peptide targeting EXOC4 K433 inhibits acetylation-dependent nuclear import, reducing KU70 methylation and restoring chemoradiotherapy sensitivity in preclinical models. Collectively, our findings identify the p300-EXOC4-KU70 axis as a critical mediator of chemoradiotherapy resistance and a promising therapeutic target.

DOI: https://doi.org/10.1038/s41418-026-01705-w