Details of a Researcher - Soga, Tomoyoshi

Papers - Soga, Tomoyoshi

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Glucose-activated JMJD1A drives visceral adipogenesis via α-ketoglutarate-dependent chromatin remodeling

Yang, C., Arai, M., Fuji Ariyanto, E., Zhang, J., Mirani Lubis D., Ito, R., Xie, S., Nitta, M., Kawashima, F., Ishitsuka, T., Yang, C., Suzuki, T., Komatsu, T., Sagae, H., Jin, H., Takahashi, H., Kobayashi, E., Wei, Y., Liu, B., Choi, H., Wada, Y., Tanaka T., Osawa, T., Kimura, H., Kodama, T., Aburatani, H., Tachibana, M., Shinkai, Y., Inagaki, T., Soga, T., Osbome, T.F., Yoneshiro, T., Matsumura, Y., Sakai, J.

Cell Rep. 44 ( 8 ) 116060 2025.08

Research paper (scientific journal), Joint Work, Accepted

Adipose tissue remodels via hypertrophy or hyperplasia in response to nutrient status, but the mechanisms governing these expansion modes remain unclear. Here, we identify a nutrient-sensitive epigenetic circuit linking glucose metabolism to chromatin remodeling during adipogenesis. Upon glucose stimulation, α-ketoglutarate (α-KG) accumulates in the nucleus and activates the histone demethylase JMJD1A to remove repressive histone H3 lysine 9 dimethylation (H3K9me2) marks at glycolytic and adipogenic gene loci, including Pparg. JMJD1A is recruited to pre-marked promoter chromatin via nuclear factor IC (NFIC), enabling carbohydrate-responsive element-binding protein (ChREBP) binding and transcriptional activation. This feedforward mechanism couples nutrient flux to chromatin accessibility and gene expression. In vivo, JMJD1A is essential for de novo adipogenesis and hyperplastic expansion in visceral fat under nutrient excess. JMJD1A deficiency impairs hyperplasia, exacerbates adipocyte hypertrophy, and induces local inflammation. These findings define a glucose-α-KG-JMJD1A-ChREBP axis regulating depot-specific adipogenesis and uncover a chromatin-based mechanism by which glucose metabolism governs adaptive adipose tissue remodeling.

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Mitochondria-Homing Drug Mitochonic Acid 5 Improves Barth Syndrome Myopathy in a Human-Induced Pluripotent Stem Cell Model and Barth Syndrome Drosophila Model

Tongu, Y., Kasahara, T., Matsuhashi, T., Oikawa, Y., Akimoto, R., Luo, Y., Sekine, S., Suzuki, M., Kashiwagi, H., Kanno, S., Tanaka, Y., Sato, K., Okubo, Y., Muto, A., Tokuno, H., Suzuki, C., Kawabe, C., Ishikawa, T., Watanabe, S., Kikuchi, K., Itai, S., Sato, T., Suzuki, T., Igarashi, K., Fukuda, S., Soga, T., Murayama, K., Kuranaga, E., Toyohara, T., Abe, T.

FASEB J. 39 ( 12 ) e70739 - e70739 2025.06

Research paper (scientific journal), Joint Work, Accepted

Barth syndrome (BTHS) is a rare disease caused by mutations in the tafazzin gene that affects the heart and muscles; however, to date, no clinically effective drugs are available. In BTHS, mitochondrial function is reduced owing to changes in cardiolipin metabolism. We developed mitochonic acid 5 (MA-5), a small-molecule compound that increases ATP levels, improves mitochondrial dynamics, and is effective in treating mitochondrial and muscle diseases. Therefore, this study examined the effectiveness of MA-5 in treating BTHS. The mitochondrial functions of four isolated BTHS skin fibroblasts were examined. Human BTHS induced pluripotent stem cell (iPSC) were differentiated into myoblasts and cardiolipin metabolism and mitochondrial functions were analyzed. RNA-seq was performed to clarify the metabolic changes. Using a Drosophila melanogaster model of BTHS, the effects of MA-5 on motor performance and cardiac phenotype were examined. MA-5 improved mitochondrial function and reduced cell death due to oxidative stress in skin fibroblasts of patients with BTHS. MA-5 promoted ATP production and reduced oxidative stress in human BTHS iPS cell-derived myoblasts. RNA-seq analysis revealed that MA-5 alleviated endoplasmic reticulum stress in BTHS cells. Administration of MA-5 to BTHS Drosophila improved locomotor ability and tachycardia observed in patients with BTHS. Protein interaction analyses suggested colocalization of ATPase and the MA-5-binding protein mitofilin. These data suggested that MA-5 improves BTHS dysfunction and may serve as a novel therapeutic agent for BTHS.

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Dietary amino acids regulate Salmonella colonization via microbiota-dependent mechanisms in the mouse gut

Pickard, J., Porwollik, S., Caballero-Flores, G., Caruso, R., Fukuda, S., Soga, T., Inohara, N., McClelland, M., Nunez, G.

Nat. Commun. 16 ( 1 ) 4225 2025.05

Research paper (scientific journal), Joint Work

The gut microbiota confers host protection against pathogen colonization early after infection. Several mechanisms underlying the protection have been described, but the contributions of nutrient competition versus direct inhibition are controversial. Using an ex vivo model of Salmonella growth in the mouse cecum with its indigenous microbes, we find that nutrient limitation and typical inhibitory factors alone cannot prevent pathogen growth. However, the addition of certain amino acids markedly reverses the microbiota's ability to suppress pathogen growth. Enhanced Salmonella colonization after antibiotic treatment is ablated by exclusion of dietary protein, which requires the presence of the microbiota. Thus, dietary protein and amino acids are important regulators of colonization resistance.

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MOB1 deletion in murine mature adipocytes ameliorates obesity and diabetes

Nishio, M., Yamaguchi, K., Otani, J., Yuguchi, K., Kohno, D., Sasaki, T., Kitamura, T., Shinohara, M., Soga, T., Kawamura, K., Sasaki, A.T., Oshima, M., Hikasa, H., Woo, M., Sasaki, T., Nishina, H., Nakao, K., Maehama, T., Suzuki, A.

Proc Natl Acad Sci USA 122 ( 17 ) e2424741122 2025.04

Research paper (scientific journal), Joint Work, Accepted, ISSN 00278424

There is currently a global epidemic of obesity and obesity-related diseases such as type 2 diabetes due to decreased physical activity, excessive food intake, and/or genetic predisposition. The Hippo-YAP1 pathway has attracted attention as a potential therapeutic target because YAP1/TAZ activation in murine immature adipocytes in vitro suppresses their differentiation by inhibiting PPARγ activity. However, the role of YAP1 activation in mature adipocytes in vivo remains unclear. MOB1, whose expression is increased in obesity, is the hub of the Hippo core molecule complex and negatively regulates YAP1/TAZ activation. Therefore, we generated aMob1DKO mutant mice, which feature deficiency of Mob1a/b specifically in mature adipocytes. Compared to controls, aMob1DKO mice subjected to a high-fat diet showed beneficial changes consistent with resistance to diet-induced obesity. The mutants exhibited increases in basal lipolysis, "beiging," and energy expenditure, as well as suppression of ROS production and inflammation in white adipose tissue. Insulin sensitivity and glucose tolerance were improved, and ectopic fat accumulation was reduced. Most of these changes were dependent on the YAP1 activation observed in mature white adipose tissue of aMob1DKO mice. FGF21, which improves lipid metabolism, was upregulated directly via YAP1 activation, and many of the phenotypes seen in aMob1DKO mice were also dependent on FGF21. Thus, the aMob1DKO mouse is an interesting model for the study of the metabolic effects of diet-induced obesity and protection against diabetes. Our work suggests that a YAP1-FGF21 axis exists in adipocytes that may be a potential therapeutic target for obesity.

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Genome-wide association study of plasma amino acids and Mendelian randomization for cardiometabolic traits

Toki, R., Fushiki, S., Kojima, S., Sutoh, Y., Otsuka-Yamasaki, Y., Harada, S., Iida, M., Hirata, A., Miyagawa, N., Matsumoto, M., Edagawa, S., Miyake, A., Kuwabara, K., Hirayama, A., Sugimoto, M., Sato, A., Amano, K., Soga, T., Tomita, M., Arakawa, K., Kinoshita, K., Sakurai-Yageta, M., Tamiya, G., Ohmomo, H., Shimizu, A., Okamura, T., Takebayashi, T.

Sci. Rep. 15 ( 1 ) 14569 2025.04

Research paper (scientific journal), Accepted

Plasma amino acids (AAs) have emerged as promising biomarkers for metabolic disorders, yet their causality remains unclear. We aimed to investigate the genetic determinants of AA levels in a cohort of 10,333 individuals and their causal effects on cardiometabolic traits using Mendelian randomization (MR). Plasma levels of 20 AAs were quantified using capillary electrophoresis mass spectrometry. Genome-wide association studies were conducted using BOLT-LMM and heritability estimation via LDSC analysis. Causal effects of AAs on 11 cardiometabolic traits were examined using two-sample MR analyses. We identified 85 locus-metabolite associations across 43 genes for 18 AAs, including 44 novel loci linked to metabolic genes. Heritability for AAs was estimated at 16%. MR analysis demonstrated cystine to positively associate with systolic blood pressure (SBP) (β = 0.056, SE = 0.010), while serine indicated protective effects on SBP (β = - 0.040, SE = 0.011), diastolic BP (β = - 0.044, SE = 0.010), and coronary artery disease (odds ratio 0.888, SE = 0.028). We identified potentially novel genetic loci associated with AA levels and demonstrated robust causal associations between several AAs and cardiometabolic traits. These findings reinforce the importance of AAs as potential biomarkers and therapeutic targets in cardiometabolic health.

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Structural robustness and temporal vulnerability of the starvation-responsive metabolic network in healthy and obese mouse liver

Morita, K., Hatano, A., Kokaji, T., Sugimoto, H., Tsuchiya, T., Ozaki, H., Egami, R., Li, D., Terakawa, A., Ohno, S., Inoue, H., Inaba, Y., Suzuki, Y., Matsumoto, M., Takahashi, M., Izumi, Y., Bamba, T., Hirayama, A., Soga, T., Kuroda, Shinya

Sci. Signal. 18 ( 883 ) eads2547 2025.04

Research paper (scientific journal), Joint Work, Accepted, ISSN 19450877

Adaptation to starvation is a multimolecular and temporally ordered process. We sought to elucidate how the healthy liver regulates various molecules in a temporally ordered manner during starvation and how obesity disrupts this process. We used multiomic data collected from the plasma and livers of wild-type and leptin-deficient obese (ob/ob) mice at multiple time points during starvation to construct a starvation-responsive metabolic network that included responsive molecules and their regulatory relationships. Analysis of the network structure showed that in wild-type mice, the key molecules for energy homeostasis, ATP and AMP, acted as hub molecules to regulate various metabolic reactions in the network. Although neither ATP nor AMP was responsive to starvation in ob/ob mice, the structural properties of the network were maintained. In wild-type mice, the molecules in the network were temporally ordered through metabolic processes coordinated by hub molecules, including ATP and AMP, and were positively or negatively coregulated. By contrast, both temporal order and coregulation were disrupted in ob/ob mice. These results suggest that the metabolic network that responds to starvation was structurally robust but temporally disrupted by the obesity-associated loss of responsiveness of the hub molecules. In addition, we propose how obesity alters the response to intermittent fasting.

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Lysine-arginine imbalance overcomes therapeutic tolerance governed by the transcription factor E3-lysosome axis in glioblastoma

Jing, Y., Kobayashi, M., Shoulkamy, M.I., Zhou, M., Thi Vu, H., Arakawa, H., Sabit, H., Iwabuchi, S., Quang Vu, C., Kasahara, A., Ueno, M., Tadokoro, Y., Kurayoshi, K., Chen, X., Yan, Y., Arai, S., Hashimoto, S., Soga, T., Todo, T., Nakada, M., Hirao, A.

Nat. Commun. 16 ( 1 ) 2876 - 2876 2025.04

Research paper (scientific journal), Joint Work, Accepted

Recent advances in cancer therapy have underscored the importance of targeting specific metabolic pathways. In this study, we propose a precision nutrition approach aimed at lysosomal function in glioblastoma multiforme (GBM). Using patient-derived GBM cells, we identify lysosomal activity as a unique metabolic biomarker of tumorigenesis, controlling the efficacy of temozolomide (TMZ), a standard GBM therapy. Employing combined analyses of clinical patient samples and xenograft models, we further elucidate the pivotal role of Transcription Factor Binding To IGHM Enhancer 3 (TFE3), a master regulator of lysosomal biogenesis, in modulating malignant properties, particularly TMZ tolerance, by regulating peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC1α)-mediated mitochondrial activity. Notably, we find that lysine protects GBM cells from lysosomal stress by counteracting arginine's effects on nitric oxide production. The lysine restriction mimetic, homoarginine administration, significantly enhances the efficacy of anticancer therapies through lysosomal dysfunction. This study underscores the critical role of lysosomal function modulated by amino acid metabolism in GBM pathogenesis and treatment.

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PNPLA6 regulates retinal homeostasis by choline through phospholipid turnover

Ono, T., Taketomi, Y., Higashi, T., Sato, H., Mochizuki-Ono, C., Nagasaki, Y., Ueta, T., Miyai, T., Tokuoka, S., Oda, Y., Nishito, Y., Ono, T., Taya, C., Arata, S., Watanabe, S., Soga, T., Hirabayashi, T., Aihara, M., Murakami, M.

Nat. Commun. 16 ( 1 ) 2221 - 2221 2025.03

Research paper (scientific journal), Joint Work, Accepted

Although mutations in human patatin-like phospholipase PNPLA6 are associated with hereditary retinal degenerative diseases, its mechanistic action in the retina is poorly understood. Here, we uncover the molecular mechanism by which PNPLA6 dysfunction disturbs retinal homeostasis and visual function. PNPLA6, by acting as a phospholipase B, regulates choline mobilization from phosphatidylcholine and subsequent choline turnover for phosphatidylcholine regeneration in retinal pigment epithelial cells. PNPLA6-driven choline is supplied from retinal pigment epithelial cells to adjacent photoreceptor cells to support their survival. Inhibition of this pathway results in abnormal morphology, proliferation, metabolism, and functions of retinal pigment epithelial and photoreceptor cells, and mice with retina-specific PNPLA6 deletion exhibit retinitis pigmentosa-like retinal degeneration. Notably, these abnormalities are entirely rescued by choline supplementation. Thus, PNPLA6 plays an essential role in retinal homeostasis by controlling choline availability for phospholipid recycling and provide a framework for the development of an ophthalmic drug target for retinal degeneration.

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Dynamics of the gut microbiome in FAP patients undergoing intensive endoscopic reduction of polyp burden

Mizutani, S., Tamaki, A., Shiba, S., Salim, F., Yamada, M., Takamaru, H., Nakajima, T., Yoshida, N., Ikuta, S., Yachida, T., Shibata, T., Soga, T., Saito, Y., Fukuda, S., Ishikawa, H., Yamada, T., Yachida, S.

Gut 74 ( 2 ) 335 - 338 2025.01

Joint Work, Accepted

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Time and dose selective glucose metabolism for glucose homeostasis and energy conversion in the liver

Pan, Y., Hatano, A., Ohno, S., Morita, K., Kokaji, T., Bai, Y., Sugimoto, H., Egami, R., Terakawa, A., Li, D., Uematsu, S., Maehara, H., Fujita, S., Inoue, H., Inaba, Y., Nagano, A., Hirayama, A., Soga, T., Kuroda, S.

npj Syst. Biol. Appl. 10 ( 1 ) 107 - 107 2024.09

Research paper (scientific journal), Joint Work, Accepted

Hepatic glucose metabolism serves dual purposes: maintaining glucose homeostasis and converting glucose into energy sources; however, the underlying mechanisms are unclear. We quantitatively measured liver metabolites, gene expression, and phosphorylated insulin signaling molecules in mice orally administered varying doses of glucose, and constructed a transomic network. Rapid phosphorylation of insulin signaling molecules in response to glucose intake was observed, in contrast to the more gradual changes in gene expression. Glycolytic and gluconeogenic metabolites and expression of genes involved in glucose metabolism including glucose-6-phosphate, G6pc, and Pck1, demonstrated high glucose dose sensitivity. Whereas, glucokinase expression and glycogen accumulation showed low glucose dose sensitivity. During the early phase after glucose intake, metabolic flux was geared towards glucose homeostasis regardless of the glucose dose but shifted towards energy conversion during the late phase at higher glucose doses. Our research provides a comprehensive view of time- and dose-dependent selective glucose metabolism.

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A Supramolecular Biosensor for Rapid and High-ThroughputQuantification of a Disease-Associated Niacin Metabolite

Ueno, M., Sugiyama, H., Li, F., Nishimura, T., Arakawa, H., Chen, X., Cheng, X., Takeuchi,, S., Takeshita, Y., Takamura, T., Miyagi, S., Toyama, T., Soga, T., Masuo, Y., Kato, Y., Nakamura, H., Tsujiguchi, H., Hara, A., Tajima, A., Noguchi-Shinohara, M., Ono, K., Kurayoshi, K., Kobayashi, M., Tadokoro, Y., Kasahara, A., Shoulkamy, M.I., Maeda, K., Ogoshi, T., Hirao, A.

Anal. Chem. 96 ( 36 ) 14499 - 14507 2024.09

Research paper (scientific journal), Joint Work, Accepted

Metabolic abnormalities play a pivotal role in various pathological conditions, necessitating the quantification of specific metabolites for diagnosis. While mass spectrometry remains the primary method for metabolite measurement, its limited throughput underscores the need for biosensors capable of rapid detection. Previously, we reported that pillar[6]arene with 12 carboxylate groups (P6AC) forms host-guest complexes with 1-methylnicotinamide (1-MNA), which is produced in vivo by nicotinamide N-methyltransferase (NNMT). P6AC acts as a biosensor by measuring the fluorescence quenching caused by photoinduced electron transfer upon 1-MNA binding. However, the low sensitivity of P6AC makes it impractical for detecting 1-MNA in unpurified biological samples. In this study, we found that P6A with 12 sulfonate groups (P6AS) is a specific and potent supramolecular host for 1-MNA interactions even in biological samples. The 1-MNA binding affinity of P6AS in water was found to be (5.68 ± 1.02) × 106 M-1, which is approximately 700-fold higher than that of P6AC. Moreover, the 1-MNA detection limit of P6AS was determined to be 2.84 × 10-7 M, which is substantially lower than that of P6AC. Direct addition of P6AS to culture medium was sufficient to quantify 1-MNA produced by cancer cells. Furthermore, this sensor was able to specifically detect 1-MNA even in unpurified human urine. P6AS therefore enables rapid and high-throughput quantification of 1-MNA, and further improvement of our strategy will contribute to the establishment of high-throughput screening of NNMT inhibitors, diagnosis of liver diseases, and imaging of human cancer cells in vivo.

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Metabolomics Profiles Alterations in Cigarette Smokers and Heated Tobacco Product Users

Harada, S., Ohmomo, H., Matsumoto, M., Sata, M., Iida, M., Hirata, A., Miyagawa, N., Kuwabara, K., Kato, S., Toki, R., Edagawa, S., Sugiyama, D., Sato, A., Hirayama, A., Sugimoto, M., Soga, T., Tomita, M., Shimizu, A., Okamura, T., Takebayashi, T.

J. Epidemiol. 34 ( 9 ) 403 - 410 2024.09

Research paper (scientific journal), Joint Work, Accepted

Background: Heated tobacco products (HTPs) have gained global popularity, but their health risks remain unclear. Therefore, the current study aimed to identify plasma metabolites associated with smoking and HTP use in a large Japanese population to improve health risk assessment.

Methods: Metabolomics data from 9,922 baseline participants of the Tsuruoka Metabolomics Cohort Study (TMCS) were analyzed to determine the association between smoking habits and plasma metabolites. Moreover, alterations in smoking-related metabolites among HTP users were examined based on data obtained from 3,334 participants involved from April 2018 to June 2019 in a follow-up survey.

Results: Our study revealed that cigarette smokers had metabolomics profiles distinct from never smokers, with 22 polar metabolites identified as candidate biomarkers for smoking. These biomarker profiles of HTP users were closer to those of cigarette smokers than those of never smokers. The concentration of glutamate was higher in cigarette smokers, and biomarkers involved in glutamate metabolism were also associated with cigarette smoking and HTP use. Network pathway analysis showed that smoking was associated with the glutamate pathway, which could lead to endothelial dysfunction and atherosclerosis of the vessels.

Conclusions: Our study showed that the glutamate pathway is affected by habitual smoking. These changes in the glutamate pathway may partly explain the mechanism by which cigarette smoking causes cardiovascular disease. HTP use was also associated with glutamate metabolism, indicating that HTP use may contribute to the development of cardiovascular disease through mechanisms similar to those in cigarette use.

Keywords: electronic nicotine delivery devices; heated tobacco products; metabolomics; prevention; smoking-induced disease.

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The role of cytidine 5'-triphosphate synthetase 1 in metabolic rewiring during epithelial-to-mesenchymal transition in non-small-cell lung cancer

Nakasuka, F., Hirayama, A., Mkinoshima, H., Yano, S., Soga, T., Tabata, S.

FEBS Open Bio 14 ( 9 ) 1570 - 1583 2024.09

Research paper (scientific journal), Joint Work, Accepted

Epithelial-to-mesenchymal transition (EMT) contributes to the poor prognosis of patients with cancer by promoting distant metastasis and anti-cancer drug resistance. Several distinct metabolic alterations have been identified as key EMT phenotypes. In the present study, we further characterize the role of transforming growth factor-β (TGF-β)-induced EMT in non-small-cell lung cancer. Our study revealed that TGF-β plays a role in EMT functions by upregulation of cytidine 5'-triphosphate synthetase 1 (CTPS), a vital enzyme for CTP biosynthesis in the pyrimidine metabolic pathway. Both knockdown and enzymatic inhibition of CTPS reduced TGF-β-induced changes in EMT marker expression, chemoresistance and migration in vitro. Moreover, CTPS knockdown counteracted the TGF-β-mediated downregulation of UDP-glucuronate, glutarate, creatine, taurine and nicotinamide. These findings indicate that CTPS plays a multifaceted role in EMT metabolism, which is crucial for the malignant transformation of cancer through EMT, and underline its potential as a promising therapeutic target for preventing drug resistance and metastasis in non-small-cell lung cancer.

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Gut microbial factors predict disease severity in a mouse model of multiple sclerosis

Steimle, A., Neumann, M., Grant, E.T., Willieme, S., Sciscio, A.D., Parrish, A., Ollert, M., Miyauchi, E., Soga, T., Fukuda, S., Ohno, H., Desai, M.S.

Nat. Microbiol. 9 ( 9 ) 2244 - 2261 2024.09

Research paper (scientific journal), Joint Work, Accepted

Gut bacteria are linked to neurodegenerative diseases but the risk factors beyond microbiota composition are limited. Here we used a pre-clinical model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE), to identify microbial risk factors. Mice with different genotypes and complex microbiotas or six combinations of a synthetic human microbiota were analysed, resulting in varying probabilities of severe neuroinflammation. However, the presence or relative abundances of suspected microbial risk factors failed to predict disease severity. Akkermansia muciniphila, often associated with MS, exhibited variable associations with EAE severity depending on the background microbiota. Significant inter-individual disease course variations were observed among mice harbouring the same microbiota. Evaluation of microbial functional characteristics and host immune responses demonstrated that the immunoglobulin A coating index of certain bacteria before disease onset is a robust individualized predictor of disease development. Our study highlights the need to consider microbial community networks and host-specific bidirectional interactions when aiming to predict severity of neuroinflammation.

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FDX2, an iron-sulfur cluster assembly factor, is essential to prevent cellular senescence, apoptosis or ferroptosis of ovarian cancer cells

Miyahara, S., Ohuchi, M., Nomura, M., Hashimoto, E., Soga, T., Saito, R., Hayashi, K., Sato, T., Saito, M., Yamashita, Y., Shimada, M., Yaegashi, N., Yamada, H., Tanuma, N.

J. Biol. Chem. 300 ( 9 ) 107678 - 107678 2024.09

Research paper (scientific journal), Accepted

Recent studies reveal that biosynthesis of iron-sulfur clusters (Fe-Ss) is essential for cell proliferation, including that of cancer cells. Nonetheless, it remains unclear how Fe-S biosynthesis functions in cell proliferation/survival. Here, we report that proper Fe-S biosynthesis is essential to prevent cellular senescence, apoptosis, or ferroptosis, depending on cell context. To assess these outcomes in cancer, we developed an ovarian cancer line with conditional KO of FDX2, a component of the core Fe-S assembly complex. FDX2 loss induced global downregulation of Fe-S-containing proteins and Fe2+ overload, resulting in DNA damage and p53 pathway activation, and driving the senescence program. p53 deficiency augmented DNA damage responses upon FDX2 loss, resulting in apoptosis rather than senescence. FDX2 loss also sensitized cells to ferroptosis, as evidenced by compromised redox homeostasis of membrane phospholipids. Our results suggest that p53 status and phospholipid homeostatic activity are critical determinants of diverse biological outcomes of Fe-S deficiency in cancer cells.

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Study Profile of the Tsuruoka Metabolomics Cohort Study (TMCS)

Harada, S., Iida, M., Miyagawa, N., Hirata, A., Kuwabara, K., Matsumoto, M., Okamura, T., Edagawa, S., Kawada, Y., Miyake, A., Toki , R., Akiyama, M., Kawai, A., Sugiyama, D., Sato, Y., Takemura, R., Fukai, K., Ishibashi, Y., Kato, S., Kurihara, A., Sata, M., Shibuki, T., Takeuchi, A., Kohsaka, S., Sawano, M., Shoji, S., Izawa, Y., Katsumata, M., Oki, K., Takahashi, S., Takizawa, T., Maruya, H., Nishiwaki, Y., Kawasaki, R., Hirayama, A., Ishikawa, T., Saito, R., Sato, A., Soga, T., Sugimoto, M., Tomita, M., Komaki, S., Ohmomo, H., Ono, K., Otsuka-Yamasaki, Y., Shimizu, A., Sutoh, Y., Hozawa, A., Kinoshita, K., Koshiba, S., Kumada, K., Ogishima, S., Sakurai-Yageta, M., Tamiya, G., Takebayashi, T.

J. Epidemiol. 34 ( 8 ) 393 - 401 2024.08

Research paper (scientific journal), Joint Work, Accepted, ISSN 09175040

The Tsuruoka Metabolomics Cohort Study (TMCS) is an ongoing population-based cohort study being conducted in the rural area of Yamagata Prefecture, Japan. This study aimed to enhance the precision prevention of multi-factorial, complex diseases, including non-communicable and aging-associated diseases, by improving risk stratification and prediction measures. At baseline, 11,002 participants aged 35-74 years were recruited in Tsuruoka City, Yamagata Prefecture, Japan, between 2012 and 2015, with an ongoing follow-up survey. Participants underwent various measurements, examinations, tests, and questionnaires on their health, lifestyle, and social factors. This study uses an integrative approach with deep molecular profiling to identify potential biomarkers linked to phenotypes that underpin disease pathophysiology and provide better mechanistic insights into social health determinants. The TMCS incorporates multi-omics data, including genetic and metabolomic analyses of 10,933 participants, and comprehensive data collection ranging from physical, psychological, behavioral, and social to biological data. The metabolome is used as a phenotypic probe because it is sensitive to changes in physiological and external conditions. The TMCS focuses on collecting outcomes for cardiovascular disease, cancer incidence and mortality, disability and functional decline due to aging and disease sequelae, and the variation in health status within the body represented by omics analysis that lies between exposure and disease. It contains several sub-studies on aging, heated tobacco products, and women's health. This study is notable for its robust design, high participation rate (89%), and long-term repeated surveys. Moreover, it contributes to precision prevention in Japan and East Asia as a well-established multi-omics platform.

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Prognostic Significance of 18F-FDG PET/CT and Tumor Metabolic Changes in Patients With Pancreatic Ductal Adenocarcinoma

Shimomura, A., Oshima, M., Suto, H., Matsukawa, H., Kondo, A., Ando, Y., Kishino, T., Kumamoto, K., Sato, K., Sugimoto, M., Nagao, M., Miyatake, N., Norikane, T., Soga, T., Okano, K.

Anticancer Res. 44 ( 8 ) 3321 - 3330 2024.08

Research paper (scientific journal), Joint Work, Accepted

Background/aim: 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) is reportedly associated with the malignant potential of cancer. This study aimed to evaluate the association between FDG accumulation and tumor metabolism in pancreatic ductal adenocarcinoma (PDAC).

Patients and methods: A prognostic analysis of data from 131 patients with PDAC who underwent FDG-PET/CT before curative-intent pancreatic surgery was performed. Capillary electrophoresis-mass spectrometry (CE-MS) was used to analyze the metabolome of tumor and non-neoplastic pancreas from 80 patients. These patients were divided into two groups: low SUVmax group (SUVmax <6.09) and high SUVmax group (SUVmax ≥6.09).

Results: Carbohydrate antigen 19-9 (CA19-9), maximum standardized uptake value (SUVmax) of PET, N stage, and postoperative chemotherapy were identified as significant prognostic factors by univariate analysis. SUVmax emerged as an independent prognostic factor for overall survival [hazard ratio (HR)=1.88, p<0.05] and disease-free survival (HR=2.01, p<0.05) in multivariate analysis. Metabolic analyses confirmed that 43 metabolites significantly differed depending on the accumulation of SUV in tumors. Metabolites involved in the removal of reactive oxygen species (e.g., hypotaurine, glutathione, Met), treatment resistance (UDP-N-acetylglucosamine), and proliferation (e.g., choline, leucine, isoleucine) were increased in the high SUVmax group.

Conclusion: FDG accumulation is an important independent prognostic factor reflecting tumor activity associated with metabolic changes in cancer cells.

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Fusobacterium species are distinctly associated with patients with Lynch Syndrome colorectal cancer

Salim, F., Mizutani, S., Shiba, S., Takamaru, H., Yamada, M., Nakajima, T., Yachida, T., Soga, T., Saito, Y., Fukuda, S., Yachida, S., Yamada, T.

iScience 27 ( 7 ) 110181 - 110181 2024.07

Research paper (scientific journal), Joint Work, Accepted

Accumulating evidence demonstrates clear correlation between the gut microbiota and sporadic colorectal cancer (CRC). Despite this, there is limited understanding of the association between the gut microbiota and CRC in Lynch Syndrome (LS), a hereditary type of CRC. Here, we analyzed fecal shotgun metagenomic and targeted metabolomic of 71 Japanese LS subjects. A previously published Japanese sporadic CRC cohort, which includes non-LS controls, was utilized as a non-LS cohort (n = 437). LS subjects exhibited reduced microbial diversity and low-Faecalibacterium enterotypes compared to non-LS. Patients with LS-CRC had higher levels of Fusobacterium nucleatum and fap2. Differential fecal metabolites and functional genes suggest heightened degradation of lysine and arginine in LS-CRC. A comparison between LS and non-LS subjects prior to adenoma formation revealed distinct fecal metabolites of LS subjects. These findings suggest that the gut microbiota plays a more responsive role in CRC tumorigenesis in patients with LS than those without LS.

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Association of Nonalcoholic Fatty Liver Disease with Arterial Stiffness and its Metabolomic Profiling in Japanese Community-Dwellers

Hirata, A., Harada, S., Iida, M., Kurihara, A., Fukai, K., Kuwabara, K., Kato, S., Matsumoto, M., Sata, M., Miyagawa, N., Toki, R., Edagawa, S., Sugiyama, D., Sato, A., Hirayama, A., Sugimoto, M., Soga, T., Tomita, M., Okamura, T., Takebayashi, T.

J. Atheroscler. Thromb. 31 ( 7 ) 1031 - 1047 2024.07

Research paper (scientific journal), Joint Work, Accepted

Aims: Nonalcoholic fatty liver disease (NAFLD) is known to be associated with atherosclerosis. This study focused on upstream changes in the process by which NAFLD leads to atherosclerosis. The study aimed to confirm the association between NAFLD and the cardio-ankle vascular index (CAVI), an indicator of subclinical atherosclerosis, and explore metabolites involved in both by assessing 94 plasma polar metabolites.

Methods: A total of 928 Japanese community-dwellers (306 men and 622 women) were included in this study. The association between NAFLD and CAVI was examined using a multivariable regression model adjusted for confounders. Metabolites commonly associated with NAFLD and CAVI were investigated using linear mixed-effects models in which batch numbers of metabolite measurements were used as a random-effects variable, and false discovery rate-adjusted p-values were calculated. To determine the extent to which these metabolites mediated the association between NAFLD and CAVI, mediation analysis was conducted.

Results: NAFLD was positively associated with CAVI (coefficients [95% Confidence intervals (CI)]=0.23 [0.09-0.37]; p=0.001). A total of 10 metabolites were involved in NAFLD and CAVI, namely, branched-chain amino acids (BCAAs; valine, leucine, and isoleucine), aromatic amino acids (AAAs; tyrosine and tryptophan), alanine, proline, glutamic acid, glycerophosphorylcholine, and 4-methyl-2-oxopentanoate. Mediation analysis showed that BCAAs mediated more than 20% of the total effect in the association between NAFLD and CAVI.

Conclusions: NAFLD was associated with a marker of atherosclerosis, and several metabolites related to insulin resistance, including BCAAs and AAAs, could be involved in the process by which NAFLD leads to atherosclerosis.

Keywords: Atherosclerosis; Branched-chain amino acids; Cardio-ankle vascular index; Insulin resistance; Metabolites; Nonalcoholic fatty liver disease.

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SGLT2 inhibition eliminates senescent cells and alleviates pathological aging

Katsuumi, G., Shimizu, I., Suda, M., Yoshida, Y., Furihata, T., Joki, Y., Hsiao, CL., Jiaqi, L., Fujiki, S., Abe, M., Sugimoto, M., Soga, T., Minamino, T

Nat. Aging 4 ( 7 ) 926 - 938 2024.07

Research paper (scientific journal), Joint Work, Accepted

It has been reported that accumulation of senescent cells in various tissues contributes to pathological aging and that elimination of senescent cells (senolysis) improves age-associated pathologies. Here, we demonstrate that inhibition of sodium-glucose co-transporter 2 (SGLT2) enhances clearance of senescent cells, thereby ameliorating age-associated phenotypic changes. In a mouse model of dietary obesity, short-term treatment with the SGLT2 inhibitor canagliflozin reduced the senescence load in visceral adipose tissue and improved adipose tissue inflammation and metabolic dysfunction, but normalization of plasma glucose by insulin treatment had no effect on senescent cells. Canagliflozin extended the lifespan of mice with premature aging even when treatment was started in middle age. Metabolomic analyses revealed that short-term treatment with canagliflozin upregulated 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside, enhancing immune-mediated clearance of senescent cells by downregulating expression of programmed cell death-ligand 1. These findings suggest that inhibition of SGLT2 has an indirect senolytic effect by enhancing endogenous immunosurveillance of senescent cells.

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