bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2025–10–12
thirteen papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge
  1. Influence of obesity and IL-6 on human postprandial amino acid and protein metabolism at whole-body and tissue level.
  2. The integrated stress response suppresses antiviral RNA interference by autophagy-mediated degradation of the RNA-induced silencing complex.
  3. Pancreatic Damage in Ovarian Cancer-Associated Cachexia Is Driven by Activin A Signalling.
  4. O-GlcNAc transferase promotes immune evasion and immunotherapy resistance in uterine corpus endometrial cancer by targeting the glucocorticoid receptor.
  5. Acidosis orchestrates adaptations of energy metabolism in tumors.
  6. The IGF2BP3-FASN axis drives lipid metabolic reprogramming to promote brain colonization in non-small cell lung cancer.
  7. AMPKα2 signals amino acid insufficiency to inhibit protein synthesis.
  8. Hypoxia-induced RCOR2 promotes macrophage M2 polarization and CD8+ T-cell exhaustion by enhancing LIF transcription in hepatocellular carcinoma.
  9. Neuronal MCT2 promotes angiogenesis via lactate in the developing mouse neocortex.
  10. The promiscuous ribosomal P-stalk: a new functional portrait.
  11. STRESS-INDUCED MODULATION OF THE TUMOR MICROENVIRONMENT: MECHANISMS AND IMPLICATIONS FOR CANCER PROGRESSION.
  12. Copper exposure induces autophagy and angiogenesis in liver cell via ATF4 activation independent of TFEB.
  13. Adipocyte FMO3-derived TMAO induces WAT dysfunction and metabolic disorders by promoting inflammasome activation in ageing.
  1. J Clin Endocrinol Metab. 2025 Oct 09. pii: dgaf547. [Epub ahead of print]
    Influence of obesity and IL-6 on human postprandial amino acid and protein metabolism at whole-body and tissue level.
    Trinh Beckey, Signe Johanne Rasmussen, Mathilde Ehnhuus Brøgger-Jensen, Ana Rita Albuquerque de Almeida Tavanez, Anton Lund, Alexandra Vassilieva, Susanne Janum, Ulrik Winning Iepsen, Kirsten Møller, Bente Klarlund Pedersen, Gerrit Van Hall, Helga Ellingsgaard.
       CONTEXT: Sarcopenic obesity, the loss of muscle mass and function in people with obesity, may result from altered muscle protein synthesis and degradation. Chronic low-grade inflammation, particularly interleukin-6 (IL-6) has been implicated.
    OBJECTIVE: To assess the role of IL-6 in protein and amino acid metabolism during fasting and postprandial states in humans with healthy weight or obesity at whole-body, skeletal muscle and subcutaneous adipose tissue levels.
    METHODS: In this placebo-controlled, non-randomized, participant-blinded study, 12 men with healthy weight and 12 men with obesity received placebo (0.9% saline) or three weeks of IL-6 receptor (IL-6R) blockade with tocilizumab. Isotope dilution/incorporation techniques and arteriovenous balance measurements were applied in fasted and postprandial states. The trial was originally designed to examine IL-6 effects on fat storage (reported previously). Here, we present pre-specified exploratory outcomes on amino acid and protein turnover.
    RESULTS: Obesity was associated with reduced meal-induced muscle-protein gain driven by impaired suppression of muscle protein degradation, and with reduced appearance of amino acids from meals. In both groups, IL-6R blockade increased fasting and postprandial plasma amino acids, and reduced postprandial plasma protein synthesis without affecting skeletal muscle protein turnover. In the healthy weight group, it also increased amino acid appearance from the meal and postprandial phenylalanine oxidation.
    CONCLUSION: Obesity impairs meal-induced muscle-protein gain, through insufficient suppression of protein degradation. Basal IL-6 activity does not regulate muscle protein turnover but influences amino acid metabolism and protein synthesis in extra-muscular tissues.
    Keywords:  Adipose Tissue; Meal; Protein Turnover; Skeletal Muscle; Stable Isotopes; Tocilizumab
    DOI:  https://doi.org/10.1210/clinem/dgaf547
  2. Proc Natl Acad Sci U S A. 2025 Oct 14. 122(41): e2511857122
    The integrated stress response suppresses antiviral RNA interference by autophagy-mediated degradation of the RNA-induced silencing complex.
    Qiyu Wang, Lingyue Chen, Jiayin Wang, Zhijian Chen, Zixian Ma, Xuan Xie, Xiaohui Zeng, Yuanyuan Bie, Zhaowei Wang.
      The small interfering RNA (siRNA) pathway is a highly conserved antiviral defense mechanism in vertebrates and invertebrates. Although the core components of this pathway are well characterized, its upstream regulatory networks remain poorly understood. Here, we identify the integrated stress response (ISR) as a negative regulator of the siRNA pathway, and demonstrate that the picorna-like virus CrPV (Cricket Paralysis Virus) exploits this mechanism for immune evasion. Mechanistically, the picorna-like virus triggers the ISR through transcriptional suppression of ppp1r15, a key regulator of eukaryotic initiation factor 2α (eIF2α) dephosphorylation. ISR activation subsequently induces the autophagy-lysosomal pathway by up-regulating Atg1 transcription in an ATF4-dependent manner. This process leads to selective degradation of Argonaute 2 (Ago2) and other core components of the RNA-induced silencing complex (RISC), thereby suppressing the host RNA interference (RNAi) machinery and enhancing viral replication. Our findings uncover an unconventional immune evasion strategy employed by a picorna-like virus and establish a previously unrecognized crosstalk between the ISR and siRNA pathways.
    Keywords:  RNA interference; autophagy; integrated stress response; picorna-like virus
    DOI:  https://doi.org/10.1073/pnas.2511857122
  3. J Cachexia Sarcopenia Muscle. 2025 Oct;16(5): e70096
    Pancreatic Damage in Ovarian Cancer-Associated Cachexia Is Driven by Activin A Signalling.
    Amirhossein Abazarikia, Wonmi So, Yi Luan, Chandramohan Kattamuri, Thomas B Thompson, So-Youn Kim.
       BACKGROUND: Cancer-associated cachexia (CAC) is a severe metabolic disorder characterized by involuntary weight loss, skeletal muscle atrophy and adipose tissue depletion. It is a major contributor to morbidity and mortality in the advanced stages of various cancers. However, the impact of CAC on the pancreas remains largely unexplored.
    METHODS: We used mice with constitutively active PI3K in oocytes, generated through a Cre-inducible Pik3ca* knock-in allele driven by Gdf9-icre and performed histological and molecular analyses of the pancreas during cachexia development. Additionally, we examined pancreatic changes following ovariectomy and administration of Follistatin 288 (FST288).
    RESULTS: Mice that developed cachexia symptoms associated with granulosa cell tumour (GCT) growth exhibited significant pancreatic atrophy compared to controls (Cre+ vs. Cre- at PD83, p < 0.0001), including reduced size of individual acinar cells (102.99 ± 12.19 μm2 vs. 207.94 ± 24.85 μm2 at PD83, p < 0.0001) and acinar units (346.41 ± 169.22 μm2 vs. 1193.59 ± 136.01 μm2 at PD83, p < 0.0001), despite comparable food intake between groups. Acinar cells exhibited a decrease in zymogen granules, reduced amylase expression and diminished amylase activity in both serum (0.29 ± 0.08 vs. 1.41 ± 0.40, p < 0.001) and tissue (0.37 ± 0.14 vs. 1.05 ± 0.29, p < 0.01). In contrast, pancreatic islets remained intact, as evidenced by histological analysis and preserved insulin expression. The pancreas of PD83 Cre+ mice also developed fibrosis and acinar cell death, characterized by elevated expression of collagen IV and α-SMA, and TUNEL-positive signals in acinar cells, respectively. Ovariectomy preserved body weight (2.66 ± 1.30 g for Cre+/OVX vs. 1.60 ± 0.97 g for Cre-) compared to Cre+ mice (-3.66 g) and maintained pancreatic function, suggesting that tumour-derived factors from GCT contribute to the severity of cachexia. Acinar cells showed high expression of ACVR2B, leading to activation of downstream p-SMAD3 signalling. Accordingly, activin A directly induced acinar cell atrophy in both ex vivo cultured pancreas (79.27 ± 19.03 μm2 vs. 171.14 ± 27.01 μm2, p < 0.0001) and 266-6 acinar cells, as evidenced by reduced acinar cell size and decreased amylase production. Injection of FST288, an activin A inhibitor, rescued pancreatic acinar atrophy (252.95 ± 11.59 μm2 in Cre+/FST288 vs. 97.25 ± 12.37 μm2 in Cre+, p < 0.001) without affecting GCT tumour size. Ex vivo culture of pancreas and 266-6 acinar cells exposed to activin A confirmed that activin A directly induces pancreatic damage.
    CONCLUSIONS: These findings demonstrate pancreatic damage occurs during CAC development and highlight the critical role of activin A in this process. Targeting activin A signalling may represent a promising therapeutic strategy to mitigate cachexia in cancer patients and preserve pancreatic function.
    Keywords:  acinar cell atrophy; activin A; amylase; cachexia; follistatin 288
    DOI:  https://doi.org/10.1002/jcsm.70096
  4. J Immunother Cancer. 2025 Oct 05. pii: e011479. [Epub ahead of print]13(10):
    O-GlcNAc transferase promotes immune evasion and immunotherapy resistance in uterine corpus endometrial cancer by targeting the glucocorticoid receptor.
    Jingjing Wang, Yang Xie, Li Liu, Shuo Rong, Huanhuan Cai, Hao Zeng, Li Zhou, Keqiong Deng, Mengqiao Dai, Chao Xu, Ying Zhu, Zhibing Lu, Xuemin Song, Xiangtai Zeng, Shi Liu.
       BACKGROUND: Although some tumors respond to immune checkpoint blockade therapy, checkpoint inhibitors have been unsuccessful in treating uterine corpus endometrial cancer (UCEC), and the underlying molecular mechanisms remain unclear.
    METHODS: We investigated glucose flux regulation in UCEC cells with a focus on the hexosamine biosynthesis pathway (HBP). The role of O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) and its interaction with the glucocorticoid receptor (GR) were examined using in vitro and in vivo models. A competitive peptide was designed to disrupt the interaction between OGT and GR.
    RESULTS: We found that UCEC cells direct glucose flux to the HBP. OGT, a critical enzyme for protein O-GlcNAcylation, increased programmed death ligand-1 (PD-L1) expression while decreasing major histocompatibility complex class I (MHC-I) expression, thereby promoting immune evasion and resistance to immunotherapy. Mechanistically, OGT interacted with GR, leading to O-GlcNAcylation of GR at serine 132, which required prior phosphorylation of GR. Disruptions of the OGT-GR interaction with the competitive peptide reduced GR O-GlcNAcylation, decreased PD-L1 expression, and increased MHC-I expression. This, in turn, activated CD8+ T cell-mediated immunity against tumor cells in vitro and in vivo.
    CONCLUSIONS: Our findings reveal cross-talk between the HBP, steroid hormone pathway, and tumor immune evasion, and suggest potential strategies for sensitizing UCEC to immunotherapy.
    Keywords:  Immune Checkpoint Inhibitor; Immune modulatory; Immunotherapy; T cell; Tumor infiltrating lymphocyte - TIL
    DOI:  https://doi.org/10.1136/jitc-2025-011479
  5. Science. 2025 Oct 09. 390(6769): eadp7603
    Acidosis orchestrates adaptations of energy metabolism in tumors.
    Sven Groessl, Robert Kalis, Marteinn T Snaebjornsson, Leon Wambach, Jakob Haider, Florian Andersch, Almut Schulze, Wilhelm Palm, Johannes Zuber.
      Malignant tumors are characterized by diverse metabolic stresses, including nutrient shortages, hypoxia, and buildup of metabolic by-products. To understand how cancer cells adapt to such challenges, we conducted sequential CRISPR screens to identify genes that affect cellular fitness under specific metabolic stress conditions in cell culture and to then probe their relevance in pancreatic tumors. Comparative analyses of hundreds of fitness genes revealed that cancer metabolism in vivo was shaped by bioenergetic adaptations to tumor acidosis. Mechanistically, acidosis suppressed cytoplasmic activity of extracellular signal-regulated kinase (ERK), thereby preventing oncogene-induced mitochondrial fragmentation and promoting fused mitochondria. The resulting boost in mitochondrial respiration supported cancer cell adaptations to various metabolic stresses. Thus, acidosis is an environmental factor that alters energy metabolism to promote stress resilience in cancer.
    DOI:  https://doi.org/10.1126/science.adp7603
  6. Cell Death Dis. 2025 Oct 06. 16(1): 684
    The IGF2BP3-FASN axis drives lipid metabolic reprogramming to promote brain colonization in non-small cell lung cancer.
    Jingwei Li, Shumin Ouyang, Ziyou Lin, Keren Peng, Jiayu Yan, Minyuan Lu, Wen Ding, Jianshan Mo, Yingxue Su, Libin Wang, Peibin Yue, Jin-Jian Lu, Xiangchao Yao, Yandong Wang, Xiaolei Zhang.
      Brain metastases represent a significant cause of morbidity and mortality in non-small cell lung cancer (NSCLC), with limited therapeutic options. The unique brain microenvironment, characterized by low lipid availability, may drive NSCLC cells to adapt through lipid metabolic reprogramming. In this study, we identify a novel mechanism by which IGF2BP3-driven lipid metabolism promotes the brain colonization of NSCLC cells through the IGF2BP3-FASN axis. Elevated IGF2BP3 expression in NSCLC brain metastases correlates with poor prognosis and promotes cancer cell migration, invasion, and brain colonization by activating the lipogenesis pathway. We further identified that FASN was a downstream target of IGF2BP3 in NSCLC cells. Mechanistically, IGF2BP3 binds to FASN mRNA, enhancing its stability through RNA-binding activity. FASN is essential for neutral lipid accumulation and brain colonization, as demonstrated in vitro and in vivo. Our findings highlight the critical role of IGF2BP3 in lipid metabolism and propose that targeting IGF2BP3 may provide a promising therapeutic strategy for NSCLC brain colonization.
    DOI:  https://doi.org/10.1038/s41419-025-08006-z
  7. Cell Metab. 2025 Oct 07. pii: S1550-4131(25)00389-4. [Epub ahead of print]
    AMPKα2 signals amino acid insufficiency to inhibit protein synthesis.
    Yunzi Mao, Mei Cui, Yanfeng Jiang, Haowen Yu, Meng Wang, Gang Li, Haihui Zhang, Cheng Zhao, Yanxin Shen, Yupeng Hu, Yanpeng An, Yan Lin, Yiyuan Yuan, Pengcheng Lin, Xingdong Chen, Wei Xu, Shi-Min Zhao.
      The functional difference between the two catalytic subunits, α1 and α2, of AMP-activated protein kinase (AMPK) complexes remains elusive. Herein, we report that AMPKα2 specifically transduces amino acid insufficiency signals to protein synthesis. Low amino acid levels, high protein levels, and reduced phosphorylation of AMPKα threonine 172 (p-T172) are observed in blood samples in patients with Alzheimer's disease (AD) from a cohort of 1,000,000 Chinese individuals. Loss of α2, but not α1, recaptures these observations and induces AD-like cognitive dysfunction in mice. Mechanistically, low amino acid-activated general control nonderepressible 2 (GCN2) specifically phosphorylates α2 at T172 independent of AMP and fructose 1,6-bisphosphate to inhibit protein synthesis. α2-p-T172 loss renders protein over-synthesis and AD-pathologic protein aggregation in cells and in mouse brain. AMPK activators metformin and 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR), as well as branched-chain amino acid (BCAA) or protein restriction, α2-p-T172-dependently prevent AD-like symptoms in mice. We identify AMPKα2 as a specific amino acid abundance detector for protein synthesis.
    Keywords:  AMPK; Alzheimer’s disease; amino acids; translation
    DOI:  https://doi.org/10.1016/j.cmet.2025.09.004
  8. J Immunother Cancer. 2025 Oct 05. pii: e012314. [Epub ahead of print]13(10):
    Hypoxia-induced RCOR2 promotes macrophage M2 polarization and CD8+ T-cell exhaustion by enhancing LIF transcription in hepatocellular carcinoma.
    Wenbo Jia, Jinyi Wang, Weiming Yang, Zhijie Ding, Litao Liang, Chao Xu, Yanzhi Feng, Qingpeng Lv, Deming Zhu, Wenhu Zhao, Xiangyu Ling, Yong Yan, Xiaoming Ai, Yongping Zhou, Lianbao Kong, Wenzhou Ding.
       BACKGROUND: The hypoxic microenvironment plays a crucial role in regulating the progression of hepatocellular carcinoma (HCC) and facilitating immune evasion. It is essential to gain a more comprehensive understanding of the pathways through which hypoxia influences HCC progression and immune evasion.
    METHODS: We employed RNA sequencing, The Cancer Genome Atlas (TCGA) data analysis, clinical data analysis of HCC, and tissue microarray immunohistochemical analysis to identify key genes associated with hypoxia regulation and immune evasion. We investigated the biological functions of REST corepressor 2 (RCOR2) in tumor progression and immune evasion through mass cytometry, multiplex immunofluorescence, an orthotopic liver transplantation tumor model, in vitro co-culture systems, flow cytometry, and immunohistochemical analysis. Additionally, we used molecular techniques such as RNA sequencing, chromatin immunoprecipitation sequencing, and mass spectrometry to gain deeper insights into the potential molecular mechanisms underlying RCOR2.
    RESULTS: We found that the hypoxia-related factor RCOR2 is upregulated in HCC and is associated with a poor prognosis. RCOR2 enhances the glycolytic process in HCC cells, thereby promoting the proliferation and metastasis of HCC cells under hypoxic conditions. Additionally, RCOR2 facilitates the M2 polarization of macrophages and contributes to the exhaustion of CD8+ T cells. Mechanistically, the hypoxic microenvironment increases the expression of RCOR2 through hypoxia-inducible factor 1-alpha. Concurrently, this microenvironment inhibits the ubiquitin-mediated degradation of RCOR2 by promoting its sumoylation, which facilitates its translocation to the nucleus. The sumoylation of RCOR2 further enhances the transcriptional activity of leukemia inhibitory factor (LIF). LIF, derived from HCC, contributes to the M2 polarization of macrophages, thereby facilitating immune evasion and playing a role in resistance to programmed cell death protein 1 (PD-1) therapies.
    CONCLUSIONS: Our research reveals that the RCOR2/LIF axis within the hypoxic microenvironment of HCC plays a significant role in immune evasion and identifies novel biomarkers associated with tumor resistance to anti-PD-1 therapy. This study provides potential therapeutic targets for HCC.
    Keywords:  Hepatocellular Carcinoma; Immunotherapy; Macrophage
    DOI:  https://doi.org/10.1136/jitc-2025-012314
  9. Cell Death Differ. 2025 Oct 04.
    Neuronal MCT2 promotes angiogenesis via lactate in the developing mouse neocortex.
    Daehoon Lee, Anika Wu, Lingling Yao, Shreya Satish, Lin Mei, Wen-Cheng Xiong.
      Neural activity drives blood vessel (BV) formation and energy substrate delivery in the developing brain to meet rising metabolic demands; however, the underlying mechanisms remain poorly understood. In this study, we exposed neonatal mice to chronic whisker stimulation (WS), a paradigm known to enhance BV formation in the somatosensory (S1) cortex. Transcriptomic (RNA-seq) and spatial (RNA-scope) analyses revealed that WS upregulated monocarboxylate transporter 2 (MCT2) in cortical neurons and MCT1 in endothelial cells (ECs). These changes coincided with increased cortical lactate levels, elevated astrocytic vascular endothelial growth factor A (VEGFa), and enhanced angiogenesis. Functional experiments demonstrated that neuronal MCT2 is essential for mediating WS-induced angiogenic and metabolic responses. Mechanistically, MCT2 facilitates L-lactate influx into the cortex with or without WS, promoting lactate uptake by neurons and astrocytes. This, in turn, induces MCT2 expression in neurons and activates hypoxia-inducible factor 1α (HIF1α) and VEGFa expression in astrocytes. Together, these findings uncover a previously unrecognized role for neuronal MCT2 in regulating lactate flux, signaling, and vascular remodeling, thereby linking neural activity to metabolic adaptation and vascular development in the neonatal mouse neocortex.
    DOI:  https://doi.org/10.1038/s41418-025-01581-w
  10. Trends Cell Biol. 2025 Oct 07. pii: S0962-8924(25)00219-3. [Epub ahead of print]
    The promiscuous ribosomal P-stalk: a new functional portrait.
    Marek Tchórzewski, Barbara Michalec-Wawiórka.
      The canonical role of the ribosome is to translate the genetic code into functional proteins. Recent discoveries, however, redefine the eukaryotic ribosome, as a regulatory hub, that senses cellular cues and transmits signals to downstream pathways. The P-stalk, an integral component of the ribosomal GTPase-associated center, once viewed as translational supporter, is now emerging as a key regulatory ribosomal module. It has recently been recognized as an activator of the integrated stress response, reshaping the Gcn1/Gcn20→Gcn2 axis into the new Gcn1/Gcn20/P-stalk→Gcn2 order. The P-stalk's structural plasticity allows also the ribosome to rewire gene expression in response to cellular demands, including cytokine response. In this review, an updated functional portrait of the P-stalk is presented, encompassing both ribosome-dependent and -independent activities.
    Keywords:  Gcn2; ribosomal P-stalk; specialized ribosomes; stress response; translation
    DOI:  https://doi.org/10.1016/j.tcb.2025.09.003
  11. Exp Oncol. 2025 Oct 07. 47(2): 127-142
    STRESS-INDUCED MODULATION OF THE TUMOR MICROENVIRONMENT: MECHANISMS AND IMPLICATIONS FOR CANCER PROGRESSION.
    V Chekhun, T Burda, O Mushii, A Pavlova, T Borikun, T Zadvornyi, N Lukianova.
      Chronic stress is one of the key exogenous factors that can significantly affect tumor cell biology by disrupting the regulation of the tumor microenvironment (TME), thereby promoting the manifestation of the malignant process. Activation of the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system induced by stressors leads to the secretion of glucocorticoids and catecholamines, which contribute to the deregulation of microenvironmental components that determine the aggressiveness of malignant neoplasms. This review systematizes the current views on the impact of stress-induced signals on the immune, stromal, vascular, and metabolic components of the TME and analyzes their contribution to the formation of an aggressive tumor phenotype. Particular attention is given to the interplay between neurohumoral stress, the gut, and the intratumoral microbiome, forming a complex networked environment supporting tumor progression. Advancing the understanding of molecular interactions between stress mediators and cellular elements of the TME will provide a foundation for developing innovative therapeutic strategies targeting not only the tumor itself but also minimizing the adverse effects of stress on individual components of the TME.
    DOI:  https://doi.org/10.15407/exp-oncology.2025.02.127
  12. Toxicology. 2025 Oct 04. pii: S0300-483X(25)00257-4. [Epub ahead of print]519 154298
    Copper exposure induces autophagy and angiogenesis in liver cell via ATF4 activation independent of TFEB.
    Meng Zhang, Yi-Ge Zhang, Yu-Tian Shi, Xiao-Chuan Qu, Yu-Heng Li, Ji-Xing Miao, Guo-Ming Sun, Peng Ge, Bao-Qin Liu.
      Copper (Cu) pollution has become as a significant global environmental concern, leading to excessive Cu accumulation in humans and disrupting cellular homeostasis. As a key catalytic cofactor, Cu is involved in essential biological processes, including oxidative stress detoxification, angiogenesis, pigmentation, and peptide hormone production. However, excessive copper exposure has been linked to various cellular pathological processes. This study demonstrated that copper exposure induced autophagy in hepatocytes in a dose- and time-dependent manner, independent of starvation. Additionally, copper stimulated transcriptional activation of autophagy-lysosome-related and pro-angiogenic factors, including vascular endothelial growth factor (VEGF), predominantly through the activation of the stress-responsive protein ATF4, while bypassing the canonical transcription factor TFEB. These findings suggest that ATF4-driven autophagy and VEGF signaling may synergistically modulate paracrine communication in the liver microenvironment, potentially contributing to angiogenic processes. These findings reveal copper's impact on liver cell functions through ATF4-mediated autophagy and angiogenesis, suggesting that ATF4 could serve as a potential therapeutic target for further exploration.
    Keywords:  ATF4; Angiogenesis; Autophagy; Copper exposure; TFEB
    DOI:  https://doi.org/10.1016/j.tox.2025.154298
  13. Nat Commun. 2025 Oct 06. 16(1): 8873
    Adipocyte FMO3-derived TMAO induces WAT dysfunction and metabolic disorders by promoting inflammasome activation in ageing.
    Thashma Ganapathy, Juntao Yuan, Melody Yuen-Man Ho, Kelvin Ka-Lok Wu, Md Moinul Hoque, Baomin Wang, Xiaomu Li, Kai Wang, Martin Wabitsch, Xuejia Feng, Yongxia Niu, Kekao Long, Qizhou Lian, Yuyan Zhu, Kenneth King-Yip Cheng.
      Trimethylamine N-oxide (TMAO) contributes to cardio-metabolic diseases, with hepatic flavin-containing monooxygenase 3 (FMO3) recognized as its primary source. Here we demonstrate that elevated adipocyte FMO3 and its derived TMAO trigger white adipose tissue (WAT) dysfunction and its related metabolic disorders in ageing. In adipocytes, ageing or p53 activation upregulates FMO3 and TMAO levels. Adipocyte-specific ablation of FMO3 attenuates TMAO accumulation in WAT and circulation, leading to enhanced glucose metabolism and energy and lipid homeostasis in ageing and obese mice. These improvements are associated with reduced senescence, fibrosis and inflammation in WAT. Proteomics analysis identified TMAO-interacting proteins involved in inflammasome activation in adipocytes and macrophages. Mechanistically, TMAO binds to the central inflammasome adaptor protein ASC, promoting caspase-1 activation and interleukin-1β production. Our findings uncover a pivotal role for adipocyte FMO3 in modulating TMAO production and WAT dysfunction by promoting inflammasome activation in ageing via an autocrine and paracrine manner.
    DOI:  https://doi.org/10.1038/s41467-025-63905-1
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