bims-obesme 2025-07-13 papers

bims-obesme

Biomed News

on Obesity metabolism

Issue of 2025–07–13
fifteen papers selected by
Xiong Weng, University of Edinburgh

Thermogenic Adipose ADH5 Counteracts Age-related Metabolic Decline.
Aging disrupts hepatocyte zonation homeostasis in mice and humans.
Bone marrow neutrophil density regulates myelopoiesis during obesity and weight loss.
Evolution of growth factor signaling to the TSC complex to regulate mTORC1.
The mitochondrial NAD transporter SLC25A51 is a modulator of beta cell senescence and type 2 diabetes.
DNA methylation and demethylation in adipocyte biology: roles of DNMT and TET proteins in metabolic disorders.
Nuclear morphometrics coupled with machine learning identifies dynamic states of senescence across age.
G proteins of the G12 family expressed by POMC neurons regulate key metabolic functions.
Aberrant Mitochondrial Metabolism in Alzheimer's Disease Links Energy Stress with Ferroptosis.
Epigenetic adaptation of beta cells across lifespan and disease: age-related demethylation is advanced in type 2 diabetes.
Modeling the vertebrate regulatory sequence landscape by UUATAC-seq and deep learning.
Somatic loss-of-function mutations in CIDEB reduce hepatic steatosis by increasing lipolysis and fatty acid oxidation.
ATF3 Deficiency Exacerbates Ageing-Induced Atherosclerosis and Clinical Intervention Strategy.
A noncanonical cGAS-STING pathway drives cellular and organismal aging.
Somatic mutations in TBX3 promote hepatic clonal expansion by accelerating VLDL secretion.

bioRxiv. 2025 Jul 04. pii: 2025.07.01.662628. [Epub ahead of print]

Thermogenic Adipose ADH5 Counteracts Age-related Metabolic Decline.

Sara C Sebag, Tate Neff, Qingwen Qian, Arvand Asghari, Zhuozhi Wang, Zeyuan Zhang, Mark Li, Meihua Hao, Vitor A Lira, Hongli Sun, Matthew J Potthoff, Ling Yang.

Aging-associated decline in brown adipose tissue (BAT) function and mass contributes to energy and metabolic homeostasis disruption. Alcohol dehydrogenase 5 (ADH5) is a major denitrosylase that prevents cellular nitro-thiol redox imbalance, an essential feature of aging. However, the functional significance of BAT ADH5 in the context of aging is largely unknown. Here, we aimed to investigate the role of BAT ADH5 in protecting against age-related metabolic dysfunction. We show that aging promotes aberrant BAT protein S-nitrosylation modification and downregulates ADH5 in mice. Furthermore, BAT ADH5-deletion accelerates BAT senescence and aging-associated declines in metabolic homeostasis and cognition. Mechanistically, we found that aging inactivates BAT Adh5 by suppressing heat shock factor 1 (HSF1), a well-recognized proteostasis regulator. Moreover, pharmacologically enhancing HSF1 improved BAT senescence, metabolic decline, and cognitive dysfunction in aged mice. Together, these findings suggest that the BAT HSF1-ADH5 signaling cascade plays a key role in protecting against age-related systemic functional decline. Ultimately, unraveling the role of thermogenic adipose nitrosative signaling will provide novel insights into the interplay between BAT nitric oxide bioactivity and metabolism in the context of aging.
Highlights: Aging elevates general protein S-nitrosylation while downregulating ADH5 expression in BAT.Loss of thermogenic adipose tissue ADH5 accelerates BAT senescence and exacerbates aging-associated metabolic and cognitive dysfunctions. Disruption of HSF1-activated Adh5 in BAT contributes to aging-associated metabolic and cognitive impairments. Pharmacological targeting of BAT HSF1 alleviates aging-related BAT senescent and systemic declines.

DOI: https://doi.org/10.1101/2025.07.01.662628
Hepatology. 2025 Jul 04.

Aging disrupts hepatocyte zonation homeostasis in mice and humans.

Saloni Sinha, Qazi Ali, Tuo Zhang, Duc Huy T-Nguyen, Silvia Hanna, Jason Sethiadi, Erika Hissong, Robert E Schwartz.

   BACKGROUND AND AIMS: Aging-induced degenerative changes in the liver are not inherently pathologic but pose an increased risk for liver diseases. However, the molecular mechanisms underlying aging-induced hepatic dyshomeostasis remain incompletely characterized. Here, we investigate how aging alters liver architecture, cellular communication, and hepatocyte zonation.
APPROACH AND RESULTS: Histological analyses of aged (>24-month-old) wild-type mouse livers showed no fibrosis, but a uniform cellular enlargement compared to young (2-month-old) mouse livers. For an unbiased characterization of aging-driven changes, we used single-nucleus RNA sequencing and found that aged livers had altered cell-cell interactions and hepatocyte zonation with zone-specific transcriptomic changes. Immunostaining confirmed aging-induced expansion of ASS1+, CYP2E1+ and GS+ hepatic zones, and an aberrant expression of ASS1+-GS+ "bi-zonal" hepatocytes, causing loss of distinct zonation. Mechanistically, this breakdown was associated with downregulation of key zonation regulators (Ctnnb1, Foxo1, Tcf7l2) and compensatory alterations in Wnt and Rspo3 signaling from NPCs. To assess translational relevance, liver biopsies from young (≤25YO) and aged (>60YO) human donors were analyzed, revealing comparable zonal alterations and supporting the conservation of these aging-associated phenotypes across species.
CONCLUSION: These findings reveal that aging causes loss of distinct hepatic zonation and alters intercellular communication through widespread transcriptional and architectural remodeling of liver cell types. The emergence of bi-zonal hepatocytes and expansion of hepatic zones in aged livers represent key hallmarks of hepatic aging. Our study provides new insights into mechanisms of liver aging and may inform therapeutic strategies targeting age-associated liver dysfunction.

Keywords:  Liver; age; hepatic; snRNA-seq; zone

DOI:  https://doi.org/10.1097/HEP.0000000000001451
J Exp Med. 2025 Sep 01. pii: e20242174. [Epub ahead of print]222(9):

Bone marrow neutrophil density regulates myelopoiesis during obesity and weight loss.

Quin T Waterbury, Jin Qian, Hualong Zheng, Amanda Dirnberger, Oakley C Olson, Ruth A White, Feijing Wu, Hiroki Kobayashi, Ermanno Malagola, Yosuke Ochiai, Ruhong Tu, Biyun Zheng, Adama Diaby, Harry Nagendra, Jonathan S LaBella, Leah Zamechek, Judith Korner, Ana B Emiliano, Anthony W Ferrante, Emmanuelle Passegué, Timothy C Wang.

The bone marrow (BM) is altered in obesity to promote myeloid cell generation, but the mechanisms driving these changes remain unclear. Here, we show that obesogenic stimuli promote adipose tissue macrophages to recruit neutrophils from the BM in mice. Recruitment of BM neutrophils activates hematopoietic stem cells, which produce myeloid cells that accumulate in the circulation and drive inflammation. This recruitment is not resolved by weight loss, leading to sustained myelopoiesis in previously obese mice. Inhibiting neutrophil recruitment out of the BM in obese mice or during weight loss reduces BM myelopoiesis and adipose tissue inflammation, and improves glucose tolerance. In humans with obesity, plasma neutrophil chemokines are increased, correlate with increased insulin resistance, but do not decrease with weight loss. Our results demonstrate that neutrophil recruitment is a key mediator of myelopoiesis during obesity, and targeting this pathway is a potential strategy to improve inflammation during obesity and weight loss.

DOI: https://doi.org/10.1084/jem.20242174
Sci Signal. 2025 Jul 08. 18(894): eadw4165

Evolution of growth factor signaling to the TSC complex to regulate mTORC1.

Kun Wang, Sophie E Lockwood, Brendan D Manning.

The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) integrates signals from factors that both stimulate (exogenous growth factors) and are essential for (intracellular nutrients and energy) cellular growth. Activation of the protein kinase mTOR within mTORC1 results in the phosphorylation of downstream substrates that collectively stimulate biomass accumulation to drive cell growth. Many upstream signals, especially growth factors, regulate mTORC1 by inducing the phosphorylation of the tuberous sclerosis complex 2 (TSC2) subunit of the TSC protein complex, a conserved brake on mTORC1 activation and its promotion of cell growth. Cryo-electron microscopy studies of the TSC protein complex have revealed that this phosphoregulation of TSC2 occurs almost exclusively on residues in loops that are outside of the evolutionarily conserved core structural elements and that did not resolve in these structures. These phosphorylation-rich unstructured loops evolved with metazoans, suggesting that the regulation of mTORC1 by diverse growth factors likely evolved with the emergence of complex body plans and diverse cell types to coordinate cell growth and metabolism within and across distinct tissues. Unlike the core structure of TSC2, these loops lack disease-associated missense mutations. These features suggest that the regulatory loops on TSC2 are more amenable to evolutionary changes that enable diverse signals to converge on the TSC protein complex to regulate mTORC1.

DOI: https://doi.org/10.1126/scisignal.adw4165
bioRxiv. 2025 Apr 11. pii: 2025.04.09.647991. [Epub ahead of print]

The mitochondrial NAD transporter SLC25A51 is a modulator of beta cell senescence and type 2 diabetes.

Byung Soo Kong, Sehi L'Yi, Erika Gabriela Ramirez-Hernandez, Serin Hong, Rosa Weidenspointner, Suyeon Song, Chase Caserta, Young Min Cho, Nora Kory.

Nicotinamide adenine dinucleotide (NAD + ) is an essential redox cofactor and signaling molecule linked to age-dependent metabolic decline, with its compartmentalization regulated by the mitochondrial carrier SLC25A51. The mechanisms contributing to declining NAD + levels during aging and the consequences of altered NAD + homeostasis across tissues are poorly understood. Here, we show that SLC25A51 is upregulated in aging and aging-associated conditions, particularly in senescent cells. In a mouse model of beta-cell senescence, upregulated SLC25A51 was associated with beta-cell identity loss, senescence progression, and a reduced NAD + /NADH ratio. SLC25A51 was elevated following p16 INK4a -, replicative-, irradiation-, and H 2 O 2 -induced senescence, with NRF2 implicated as a potential transcriptional regulator. Overexpression of SLC25A51, but not a transport-dead mutant, induced senescence factors, while its deletion prevented this effect. Beta-cell-specific deletion of SLC25A51 lowered p16 INK4a levels in pancreatic islets, circulating insulin, and glucose levels, improving insulin sensitivity and indicating its role in cellular senescence and the metabolic control of beta-cell function.

DOI: https://doi.org/10.1101/2025.04.09.647991
Front Endocrinol (Lausanne). 2025 ;16 1591152

DNA methylation and demethylation in adipocyte biology: roles of DNMT and TET proteins in metabolic disorders.

Lijiao Wu, Xiangjin Wang, Luling Wang, Shuyan Li, Qiu Chen.

  Adipocytes play a crucial role in regulating energy metabolism throughout the body. Dysfunctional adipocyte biology is a primary factor in the development of metabolic disorders associated with obesity and type 2 diabetes. Over the past decades, the role of epigenetic mechanisms, particularly DNA methylation, in the development and regulation of adipocytes has been extensively elucidated. These mechanisms influence numerous biological processes in adipose tissue and adipocytes, including lipogenesis and lipid metabolism. With the discovery of the active DNA demethylation mechanism centered on ten-eleven translocation (TET) proteins, a growing body of evidence sug-gests that DNA demethylation mechanisms also profoundly influence various aspects of adipocyte biology and regulate cellular differentiation and function by altering the methylation status of genes. Following the discovery of active DNA demethylation mechanisms mediated by TET proteins, a growing body of evidence indicates that these mechanisms profoundly influence multiple aspects of adipocyte biology. Specifically, these mechanisms regulate cellular differentiation and function by altering the methylation status of key genes involved in adipogenesis and metabolism. A precise and detailed understanding of the mechanisms underlying DNA demethylation in adipocyte biology is imperative for the identification of novel interventional therapies targeting adipocyte gene methylation and demethylation. This review examines the specific molecular mechanisms and significance of passive and active DNA demethylation in adipocyte biology, focusing on the DNA methyltransferase family and TET proteins. It summarizes crosstalk mechanisms involving DNA methyltransferases, highlights the multiple action pathways of TET proteins, and reveals the potential of additional intervention pathways. This review aims to provide an updated theoretical basis for promising therapeutic targets.

Keywords:  DNA demethylation; DNA methyltransferase family; adipocyte biology; epigenetic mechanisms; ten-eleven translocation proteins

DOI:  https://doi.org/10.3389/fendo.2025.1591152
Nat Commun. 2025 Jul 07. 16(1): 6231

Nuclear morphometrics coupled with machine learning identifies dynamic states of senescence across age.

Sahil A Mapkar, Sarah A Bliss, Edgar E Perez Carbajal, Sean H Murray, Zhiru Li, Anna K Wilson, Vikrant Piprode, You Jin Lee, Thorsten Kirsch, Katerina S Petroff, Fengyuan Liu, Michael N Wosczyna.

Cellular senescence is an irreversible state of cell cycle arrest with a complex role in tissue repair, aging, and disease. However, inconsistencies in identifying cellular senescence have led to varying conclusions about their functional significance. We developed a machine learning-based approach that uses nuclear morphometrics to identify senescent cells at single-cell resolution. By applying unsupervised clustering and dimensional reduction techniques, we built a robust pipeline that distinguishes senescent cells in cultured systems, freshly isolated cell populations, and tissue sections. Here we show that this method reveals dynamic, age-associated patterns of senescence in regenerating skeletal muscle and osteoarthritic articular cartilage. Our approach offers a broadly applicable strategy to map and quantify senescent cell states in diverse biological contexts, providing a means to readily assess how this cell fate contributes to tissue remodeling and degeneration across lifespan.

DOI: https://doi.org/10.1038/s41467-025-60975-z
Sci Adv. 2025 Jul 11. 11(28): eadu1670

G proteins of the G12 family expressed by POMC neurons regulate key metabolic functions.

Dhanush Haspula, Zhenzhong Cui, Srinivas Pittala, Yinghong Cui, Huiyan Lu, Yan Xiong, Jian Jin, Oksana Gavrilova, Eunsang Hwang, Jason Ajwani, Bryan Portillo, Kevin W Williams, Asuka Inoue, Jürgen Wess.

Proopiomelanocortin (POMC) neurons play a key role in maintaining glucose and energy homeostasis. POMC neurons express many heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors that are linked to different functional classes of G proteins. The potential role of G12/13 in regulating the function of central POMC neurons remains unknown. To address this question, we used a chemogenetic approach to selectively stimulate G12/13 signaling in POMC neurons. We found that receptor-mediated activation of G12/13 signaling in POMC neurons caused notable improvements in glucose homeostasis in lean and obese mice. Stimulation of G12/13 signaling in POMC neurons also enhanced the physiological actions of leptin. Studies with G12/13 knockout mice showed that G12/13 signaling in POMC neurons mediated the beneficial metabolic effects of lorcaserin, an appetite-suppressant drug that selectively activates serotonin 5-HT2C receptors. These findings indicate that G12/13-coupled receptors expressed by POMC neurons represent potential targets for advanced classes of antidiabetic and appetite-suppressant drugs.

DOI: https://doi.org/10.1126/sciadv.adu1670
Adv Sci (Weinh). 2025 Jul 08. e04175

Aberrant Mitochondrial Metabolism in Alzheimer's Disease Links Energy Stress with Ferroptosis.

Francesca Alves, Darius Lane, Adam Wahida, Md Jakaria, Pawel Kalinowski, Adam Southon, Abdel Ali Belaidi, Teresa Samperi-Esteve, Triet Phu Minh Nguyen, Peng Lei, Marcus Krueger, Stefan Mueller, Marcus Conrad, Puja Agarwal, Sue E Leurgans, Julie Schneider, Ashley I Bush, Scott Ayton.

  Alzheimer's disease (AD) is defined by β-amyloid plaques and tau-containing neurofibrillary tangles, but the ensuing cellular derangements that culminate in neurodegeneration remain elusive. Here, a mechanistic link between two AD pathophysiological hallmarks: energy insufficiency and oxidative stress is revealed. It is demonstrated that mitochondrial function and glutathione (GSH) flux are coupled, impacting neuronal ferroptosis susceptibility. Analysis of proteomic data from the inferior temporal cortex of 625 subjects along a continuum of clinical and pathological changes in AD, reveals a prominent depletion of mitochondrial proteins. Biogenetic insufficiency in AD is reflected by a concurrent loss of GSH, which requires 2 ATP for its synthesis, and genetic and pharmacologic ATP depletion models confirm that ATP is rate-limiting for GSH. Accordingly, an unbiased association analysis uncovers mitochondrial proteins in positive correlation with total GSH (t-GSH) in AD subjects. But mitochondria also consume GSH via the SLC25A39 transporter. It is found that mitochondrial inhibition either increases or decreases ferroptosis susceptibility in cellular models, depending on contextual factors that dictate whether mitochondria act as a net GSH producer or consumer, respectively. Mitochondria therefore control GSH flux, and loss of energy output is consequently demonstrated as a liability for ferroptosis in AD.

Keywords:  ATP; alzheimer's disease; bioenergetics; ferroptosis; glutathione; mitochondria; neurodegeneration

DOI:  https://doi.org/10.1002/advs.202504175
bioRxiv. 2025 Jul 05. pii: 2025.07.02.662814. [Epub ahead of print]

Epigenetic adaptation of beta cells across lifespan and disease: age-related demethylation is advanced in type 2 diabetes.

Elisabetta Manduchi, Hélène C Descamps, Jinping Liu, Jonathan Schug, Tong Da, Deeksha Lahori, Hilana El-Mekkoussi, Michelle Lee, Eseye Feleke, Diana Bernstein, Chengyang Liu, Ali Naji, Benjamin Glaser, Klaus H Kaestner, Dana Avrahami.

Although the prevalence of type 2 diabetes (T2D) increases with age, most adults maintain normoglycemia despite rising insulin resistance, largely due to the adaptive capacity of pancreatic beta cells to meet increased metabolic demand. However, persistent insulin resistance can lead to beta cell dysfunction and T2D onset. Here, leveraging cell-type-specific methylome data from the Human Pancreas Analysis Program (HPAP), we investigate the epigenomic basis of beta cell adaptation by mapping genome-wide DNA methylation (DNAm) patterns across the human lifespan. In healthy donors, we identify progressive age-related demethylation enriched in cis - regulatory elements at beta cell identity and function genes, suggesting that epigenetic remodeling supports functional adaptation to metabolic demand over time. In contrast, alpha cells show the opposite trajectory, with subtle, age-related hypermethylation. In T2D beta but not alpha cells we observed further demethylation compared to healthy controls, underscoring a unique capacity of beta cells to respond to changes in metabolic demand. Together, our findings suggest that DNAm remodeling in healthy beta cells reflects a long-term adaptation to metabolic demand, which in T2D is accelerated as part of a compensatory response that ultimately fails under sustained insulin resistance.

DOI: https://doi.org/10.1101/2025.07.02.662814
Cell. 2025 Jul 01. pii: S0092-8674(25)00686-5. [Epub ahead of print]

Modeling the vertebrate regulatory sequence landscape by UUATAC-seq and deep learning.

Xiaoping Han, Hanyu Wu, Xueyi Wang, Daiyuan Liu, Yuting Fu, Lei Yang, Renying Wang, Peijing Zhang, Jingjing Wang, Lifeng Ma, Jizhong Mao, Lina Zhou, Siqi Wang, Xinlian Zhang, Mengmeng Jiang, Xinru Wang, Guoxia Wen, Danmei Jia, Guoji Guo.

  The regulatory sequences of vertebrate genomes remain incompletely understood. To address this, we developed an ultra-throughput, ultra-sensitive single-nucleus assay for transposase-accessible chromatin using sequencing (UUATAC-seq) protocol that enables the construction of chromatin accessibility landscapes for one species in a 1-day experiment. Using UUATAC-seq, we mapped candidate cis-regulatory elements (cCREs) across five representative vertebrate species. Our analysis revealed that genome size differences across species influence the number but not the size of cCREs. We introduced Nvwa cis-regulatory element (NvwaCE), a mega-task deep-learning model designed to interpret cis-regulatory grammar and predict cCRE landscapes directly from genomic sequences with high precision. NvwaCE demonstrated that regulatory grammar is more conserved than nucleotide sequences and that this grammar organizes cCREs into distinct functional modules. Moreover, NvwaCE accurately predicted the effects of synthetic mutations on lineage-specific cCRE function, aligning with causal quantitative trait loci (QTLs) and genome editing results. Together, our study provides a valuable resource for decoding the vertebrate regulatory language.

Keywords:  NvwaCE; UUATAC-seq; cCRE; chromatin accessibility landscape; deep learning; genome editing; genomics; mutation effect; regulatory sequence; snATAC-seq

DOI:  https://doi.org/10.1016/j.cell.2025.06.020
J Hepatol. 2025 Jul 04. pii: S0168-8278(25)02320-7. [Epub ahead of print]

Somatic loss-of-function mutations in CIDEB reduce hepatic steatosis by increasing lipolysis and fatty acid oxidation.

Qiyu Zeng, Satish Patel, Xun Wang, Meng-Hsiung Hsieh, Zhijie Li, Xiongzhao Ren, Jingjing Wang, Dohun Kim, Shili Li, Xinping Gu, Greg Mannino, Gianna Maggiore, Xiangyi Fang, Lin Li, Min Zhu, Mengmeng Wang, Boyuan Li, Amaey Bellary, Koini Lim, Zhetuo Qi, Pushpa Pushpa, Mandour Omer Mandour, Vladimir Saudek, Tripti Sharma, Yu Zhang, Gerta Hoxhaj, Prashant Mishra, Purva Gopal, Peter Campbell, Matthew Hoare, David B Savage, Hao Zhu.

   BACKGROUND & AIMS: Somatic and germline CIDEB mutations are associated with protection from chronic liver diseases. The mechanistic basis and whether CIDEB suppression would be an effective therapy against fatty liver disease remain unclear.
METHODS: 21 CIDEB somatic mutations were introduced into cells to assess functionality. In vivo screening was used to trace Cideb mutant clones in mice fed normal chow, western (WD), and choline-deficient, L-amino acid-defined, high-fat (CDA-HFD) diets. Constitutive and conditional Cideb knockout mice were generated to study Cideb in liver disease. Isotope tracing was used to evaluate fatty acid oxidation and de novo lipogenesis. Transcriptomics, lipidomics, and metabolic analyses were utilized to explore molecular mechanisms. Double knockout models (Cideb/Atgl and Cideb/Pparα) tested mechanisms underlying Cideb loss.
RESULTS: Most CIDEB mutations showed that they impair function, and lineage-tracing showed that loss-of-function clones were positively selected with CDA-HFD, but not all fatty liver inducing diets. Cideb KO mice were protected from WD, CDA-HFD, and alcohol diets, but had the greatest impact on CDA-HFD induced liver disease. Hepatocyte-specific Cideb deletion could ameliorate disease after metabolic dysfunction-associated steatotic liver disease (MASLD) establishment, modeling the impact of therapeutic siRNAs. Cideb loss protected livers via increased β-oxidation, specifically through ATGL and PPARα activation.
CONCLUSIONS: Cideb deletion is more protective in some types of fatty liver disease. β-oxidation is an important component of the Cideb protective mechanism. CIDEB inhibition represents a promising approach, and somatic mutations in CIDEB might predict the patient populations that might benefit the most.
IMPACT AND IMPLICATIONS: It is not clear why somatic and germline CIDEB mutations are protective in MASLD. Cideb mutations are predominantly loss of function, and Cideb-deficient clones selectively expand in specific dietary contexts such as CDA-HFD-induced MASLD. Consistently, liver-wide deletion of Cideb ameliorates MASLD most profoundly after CDA-HFD feeding. Mechanistically, Cideb deficiency enhances hepatic fatty acid β-oxidation via ATGL and PPARα activation. These findings suggest that CIDEB inhibition might be most effective in patients with the subtypes of MASLD that promote the expansion of CIDEB mutant clones.

Keywords:  CIDEB; fatty liver disease; in vivo screening; somatic mutations; β-oxidation

DOI:  https://doi.org/10.1016/j.jhep.2025.06.021
Adv Sci (Weinh). 2025 Jul 11. e02249

ATF3 Deficiency Exacerbates Ageing-Induced Atherosclerosis and Clinical Intervention Strategy.

Hao Nie, Tianyi Ji, Zixin Wan, Jie Huang, Han Li, Lingjiao Zou, Zhen Yang, Jiarui Li, Yuqi Guan, Lei Ruan, Jinhua Yan, Cuntai Zhang.

  Vascular smooth muscle cell (VSMC) senescence is a pivotal driver of atherosclerosis (AS), but molecular links to ageing-related dysfunction are unclear. It is aimed to identify regulators of VSMC senescence and develop clinical interventions for ageing-related AS. Using single-cell RNA sequencing of human atherosclerotic carotid arteries and immunofluorescence validation, activating transcription factor 3 (ATF3) is identified as central to VSMC senescence. Mechanistic studies employ SMC-specific ATF3 knockout mice, CUT&Tag-seq, RNA/protein interaction assays, and m6A epitranscriptomic analyses. To bridge discovery to therapy, high-throughput virtual screening is performed for ATF3-targeting compounds and functionally validated hits. ATF3 deficiency in VSMCs accelerates ageing-induced AS by promoting senescence. Multi-omics showed ATF3 activates ATG7, triggering autophagy, while cytoplasmic ATG7 enhances ATF3 nuclear translocation, establishing a positive feedback loop. Ageing increases m6A methylation and decreases the stability of Atf3 mRNA. Terazosin (TZ) diminishes the interaction between YTH N6-methyladenosine RNA binding protein F2 (YTHDF2) and Atf3 mRNA, helping to preserve Atf3 mRNA stability. TZ is a promising therapeutic strategy for delaying VSMC senescence and preventing AS. ATF3 protects against VSMC senescence and AS by orchestrating autophagy via a novel ATF3-ATG7 amplification loop. Repurposing TZ to stabilize ATF3 offers a translatable approach to combat ageing-driven cardiovascular disease.

Keywords:  activated transcription factor 3; atherosclerosis; autophagy; terazosin; vascular smooth muscle cells senescence

DOI:  https://doi.org/10.1002/advs.202502249
Proc Natl Acad Sci U S A. 2025 Jul 15. 122(28): e2424666122

A noncanonical cGAS-STING pathway drives cellular and organismal aging.

Rafael Cancado de Faria, Lilian N D Silva, Barbara Teodoro-Castro, Kyle S McCommis, Elena V Shashkova, Susana Gonzalo.

  Accumulation of cytosolic DNA has emerged as a hallmark of aging, inducing sterile inflammation. Stimulator of interferon genes (STING) protein translates the sensing of cytosolic DNA by cyclic-GMP-AMP synthase (cGAS) into an inflammatory response. However, the molecular mechanisms whereby cytosolic DNA-induced cGAS-STING pathway leads to aging remain poorly understood. We show that STING does not follow the canonical pathway of activation in human fibroblasts passaged (aging) in culture, senescent fibroblasts, or progeria fibroblasts (from Hutchinson-Gilford progeria syndrome patients). Despite cytosolic DNA buildup, features of the canonical cGAS-STING pathway like increased cGAMP production, STING phosphorylation, and STING trafficking to perinuclear compartment are not observed in progeria/senescent/aging fibroblasts. Instead, STING localizes at endoplasmic reticulum, nuclear envelope, and chromatin. Despite the nonconventional STING behavior, aging/senescent/progeria cells activate inflammatory programs such as the senescence-associated secretory phenotype and the interferon response, in a cGAS and STING-dependent manner, revealing a noncanonical pathway in aging. Importantly, progeria/aging/senescent cells are hindered in their ability to activate the canonical cGAS-STING pathway with synthetic DNA, compared to young cells. This deficiency is rescued by activating vitamin D receptor signaling, unveiling mechanisms regulating the cGAS-STING pathway in aging. Significantly, in HGPS, inhibition of the noncanonical cGAS-STING pathway ameliorates cellular hallmarks of aging, reduces tissue degeneration, and extends the lifespan of progeria mice. Our study reveals that a new feature of aging is the progressively reduced ability to activate the canonical cGAS-STING pathway in response to cytosolic DNA, triggering instead a noncanonical pathway that drives senescence/aging phenotypes.

Keywords:  aging; cGAS; cytosolic DNA; senescence-associated secretory phenotype; stimulator of interferon genes

DOI:  https://doi.org/10.1073/pnas.2424666122
J Clin Invest. 2025 Jul 10. pii: e191855. [Epub ahead of print]

Somatic mutations in TBX3 promote hepatic clonal expansion by accelerating VLDL secretion.

Gregory Mannino, Gabriella Quinn, Min Zhu, Zixi Wang, Xun Wang, Boyuan Li, Meng-Hsiung Hsieh, Thomas Mathews, Lauren Zacharias, Wen Gu, Purva Gopal, Natalia Brzozowska, Peter Campbell, Matt Hoare, Glen Liszczak, Hao Zhu.

  Somatic mutations that increase clone fitness or resist disease are positively selected, but the impact of these mutations on organismal health remains unclear. We previously showed that Tbx3 deletion increases hepatocyte fitness within fatty livers. Here, we detected TBX3 somatic mutations in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). In mice, Tbx3 deletion protected against, whereas Tbx3 overexpression exacerbated MASLD. Tbx3 deletion reduced lipid overload by accelerating VLDL secretion. Choline deficient diets, which block VLDL secretion, abrogated this protective effect. TBX3 transcriptionally suppressed the conventional secretory pathway and cholesterol biosynthesis. Hdlbp is a direct target of TBX3 that is responsible for the altered VLDL secretion. In contrast to wild-type TBX3, the TBX3 I155S and A280S mutations found in patients failed to suppress VLDL secretion. In conclusion, TBX3 mutant clones expand during MASLD through increased lipid disposal, demonstrating that clonal fitness can benefit the liver at the cost of hyperlipidemia.

Keywords:  Cell biology; Gastroenterology; Hepatitis

DOI:  https://doi.org/10.1172/JCI191855