Details of a Researcher - Soga, Tomoyoshi

Papers - Soga, Tomoyoshi

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Elevated glucose metabolism via the hexosamine biosynthesis pathway: A metabolic signature of high-fluorodeoxyglucose-uptake lung adenocarcinoma

Watanabe, H., Makinoshima, H., Kanauchi, N., Kabasawa, T., Suzuki, J., Takamori, S., Sasage, T., Abe, K., Hoshijima, K., Uchida, T., Soga, T., Shiono, S.

Surg. Today 56 ( 8 ) 1645 - 1656 2026.08

Joint Work, Accepted, ISSN 09411291

Purpose
To evaluate hexosamine biosynthetic pathway (HBP) involvement in high-fluorodeoxyglucose (FDG)-uptake lung adenocarcinoma.

Methods
We conducted metabolomic analysis to evaluate the HBP in patients with lung adenocarcinoma, who underwent preoperative 18-FDG positron emission tomography. Capillary electrophoresis-time-of-flight mass spectrometry was done to obtain 511 small-molecule metabolite spectra, and a principal component analysis was performed.

Results
We examined 80 tissue samples: 40 tumor-adjacent non-tumor tissue samples and 40 resected lung adenocarcinomas. The principal component analysis confirmed good clustering between the tumor and non-tumor tissues. The non-tumor tissues comprised uniform materials, whereas the tumor tissues comprised a mixture of materials. Heatmaps for 50 metabolites revealed lower glucose and citrate levels and higher levels of lactate, glycolysis metabolites, succinate, fumarate, adenosine di- and -monophosphate, and all essential amino acids in the tumor tissues than the non-tumor tissues. HBP intermediate and uridine diphosphate N-acetylglucosamine levels were also higher in the tumor tissues. Both lactate and HBP intermediate levels were higher in hypermetabolic tumor tissues (standardized uptake value ≥ 3) than in non-hypermetabolic tumor tissues (standardized uptake value < 3). Low-FDG-uptake cells showed strong expression for glucose transporter SLC2A1 and weak expression for O-linked N-acetylglucosamine, whereas high-FDG-uptake cells showed strong expression for both markers.

Conclusions
Hypermetabolic adenocarcinoma may be associated with intensified glycolysis and HBP activation.

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Nicotinic Acid Restriction Enhances the Therapeutic Benefit of NAMPT Inhibition in Small-Cell Lung Cancer Models

Tsurumi, K., Nomura, M., Ouchi, M., Yagishita, S., Kikuchi, N., Sato, T., Morita, M., Yamashita, Y., Hayashi, K., Soga, T., Hamada, A., Fukuhara, T., Tanuma, N.

Cancer Sci. online 2026.07

Research paper (scientific journal), Accepted

Small-cell lung cancer (SCLC) is an aggressive malignancy with limited therapeutic options. We previously showed that nicotinic acid riboside (NAR) sustains NAD biosynthesis in vivo and compensates for NAMPT inhibition in SCLC models. Here, we evaluated combining NAMPT inhibition with dietary nicotinic acid (NA) restriction to suppress NAR-dependent NAD biosynthesis. This combination showed enhanced antitumor activity consistent with synthetic lethality in SCLC CDX models and showed robust efficacy in PDX models, including those derived from chemotherapy-refractory tumors. In most CDX models examined, combination therapy showed greater antitumor activity than standard chemotherapy with cisplatin and etoposide. Although we did observe transient leukopenia, the treatment was otherwise better tolerated than chemotherapy, with less impact on body weight and platelet counts. These findings support NAD metabolism-targeted therapy as a promising strategy to treat SCLC.

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Plasma metabolomic signatures of heterogeneous multimorbidity trajectories in ageing: a population-based cohort study

Toki, R., Iba, C., Omoto, Y., Matsumoto, M., Iida, M., Edagawa, S., Harada, S., Hirata, A., Miyagawa, N., Miyake, A., Hirayama, A., Sugimoto, M., Sato, A., Amano, K., Soga, T., Arakawa, K., Takebayashi, T.

Geroscience online 2026.07

Joint Work, Accepted, ISSN 25092715

Age-related disease burden accumulates heterogeneously from later midlife to older age, but the biology underlying these divergent trajectories is poorly understood. We analysed 7199 adults aged 40 years and over in the Tsuruoka Metabolomics Cohort Study, Japan, with baseline fasting plasma metabolomics (94 metabolites measured by capillary electrophoresis-mass spectrometry) and linked health insurance claims. Monthly cumulative Charlson Comorbidity Index scores were constructed from aligned cohort entry to 60 months to capture accumulation of newly documented Charlson conditions after follow-up start. K-means clustering identified six trajectories of claims-recorded disease burden, and ordinal logistic regression related metabolites to ordered trajectory severity with adjustment for demographic and lifestyle factors. Six trajectories ranged from minimal accumulation to rapid progression. Nineteen metabolites were associated with greater trajectory severity after false discovery rate correction. Glutamate showed the strongest positive association (odds ratio, 1.18 per standard deviation; 95% confidence interval, 1.12-1.24), whereas cysteine-glutathione disulfide showed the strongest inverse association (odds ratio, 0.89; 95% confidence interval, 0.86-0.93). Eighteen of these metabolites were also associated with time to first newly documented Charlson disease. Disease-specific analyses linked glutamate to diabetes with complications, mild liver disease, and cerebrovascular disease. Exploratory cluster-specific analyses identified hippurate as a distinctive marker of a late-acceleration trajectory. These findings implicate amino acid metabolism, redox balance, and microbiome-host interactions as candidate biological pathways underlying heterogeneous patterns of age-related disease accumulation, and warrant replication in independent cohorts. These signals may inform biomarker development for accelerated disease-burden accumulation.

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Metabolic buffering restricts phenotype switching in melanoma

Ramírez-Sánchez, A., Jociles-Ortega, M., García-Martínez, J.M., Torrens-Martínez, I., Martínez-Useros, J., Louphrasitthiphol, P., Sweeney, M.I., Morente-Carrasco, A., Ruiz-Reyes, S., Redondo-Díaz, N., Olmos-De Blas, T., Fernández-Aceñero, M.J., Rodriguez-López, J.N., Soga, T., White, R.M., Goding, C.R., Sanchez-Del-Campo, L., García-Jiménez, C., Chocarro-Calvo, A.

EMBO J. online 2026.07

Research paper (scientific journal), Accepted, ISSN 02614189

The impact of the metabolic microenvironment on epigenetically plastic cancer cells underpins phenotypic heterogeneity, a major cause of metastasis and therapy resistance. Nutrient limitation is a key microenvironmental stress, and can cause cells to transition from proliferative to invasive phenotypes, however, whether cancer cells have the capacity to delay phenotype switching remains unknown. Here, using melanoma as a model, we reveal that the ability to buffer glucose availability by accumulating and mobilizing glycogen can determine cancer cell phenotypic transitions. While proliferating cells contain high levels of glycogen, invasive cells are marked by depleted glycogen stores. Accordingly, the inability to store and metabolize glycogen leads to phenotype instability and a switch from proliferation to invasion. The amount of stored glycogen inversely correlates with tissue invasion depth in primary melanomas, and reduced expression of the glycogen phosphorylases PYGB/L and phosphoglucomutase 1 (PGM1) is associated with worse patient survival. Together, we identify metabolic glucose buffering as a determinant of invasive phenotype transitions in skin cancer, suggesting similar paradigms in other cancer types.

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2,3-Pyridinedicarboxylate Is Associated with Shorter Recurrence-Free Survival in Patients with Hypopharyngeal Squamous Cell Carcinoma

Takase, H., Fujisawa, T., Hayashi, R., Makinoshima, H., Suzuki, Y., Soga, T., Fujii, S.

Pathobiology 93 ( 2 ) 72 - 86 2026.06

Research paper (scientific journal), Joint Work, Accepted, ISSN 10152008

Introduction: Metabolites are associated with the biology of cancer; however, no metabolites related to prognosis have been identified in head and neck cancer. This study aimed to identify metabolites associated with prognosis in patients with hypopharyngeal squamous cell carcinoma (HPSCC).

Methods: Fifty-two patients who underwent surgery for HPSCC were included and randomly divided into test and validation cohorts of 26 patients each for further metabolome analysis using capillary electrophoresis/mass spectrometry on tumor and non-tumor tissues of the hypopharynx. Twenty-two patients who received adjuvant therapy after surgery were included. The receiver operating characteristic (ROC) and univariate and multivariate analyses were used to explore the relationship between recurrence-free survival (RFS), clinicopathological factors, and differentiated metabolites.

Results: ROC analysis revealed six metabolites significantly associated with RFS in both cohorts, and multivariate analysis indicated that 2,3-pyridinedicarboxylate was a significantly independent poorer prognostic factor in the cohorts including patients with HPSCC without any adjuvant therapies (p = 0.017).

Conclusion: 2,3-Pyridinedicarboxylate, involved in NAD+ metabolism and genomic stability, suggests the possibility of developing molecular-targeted drugs for the production of metabolites related to prognosis. This study identifies novel prognostic metabolites and their associated metabolic pathways in HPSCC, highlighting potential therapeutic targets for treatment.

Keywords: 2,3-Pyridinedicarboxylate; Hypopharyngeal squamous cell carcinoma; Metabolites; Recurrence-free survival.

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Paired tumor–normal metabolomic profiling reveals alterations in choline phospholipid precursor metabolism in biliary tract cancer

Suto, H., Kumamoto, K., Nagao, M., Furuichi, Y., Fuke, T., Matsukawa, H., Ando, Y., Oshima, M., Kobayashi, K., Kobara, H., Soga, T., Okano, K.

J. Gastroenterol. online 2026.06

Research paper (scientific journal), Joint Work, ISSN 09441174

Background: The metabolic landscape of biliary tract cancer (BTC) remains poorly characterized. This study aimed to identify tumor-specific metabolic alterations in BTC using paired tumor and adjacent normal tissues.

Methods: Metabolomic profiling was performed on paired tumor and adjacent normal tissues from 71 patients with BTC using capillary electrophoresis time-of-flight mass spectrometry. Differential metabolites were identified using paired statistical analysis with false discovery rate correction. Pathway enrichment analysis was conducted using the Kyoto Encyclopedia of Genes and Genomes database.

Results: Seventeen metabolites were significantly altered between tumor and normal tissues. Pathway analysis identified glycerophospholipid metabolism as the most enriched pathway, driven by water-soluble precursor and intermediate metabolites, including phosphorylcholine, CDP-choline, and ethanolamine phosphate. Hierarchical clustering demonstrated partially distinct metabolic patterns between tumor and normal tissues, with substantial inter-sample variability observed among tumor samples. Metabolites related to amino sugar and nucleotide sugar metabolism were also increased in tumor tissues. Additional pathways, including nicotinate and nicotinamide metabolism and arginine and proline metabolism, were also enriched. Principal component analysis showed partial separation between tumor and normal samples, indicating global metabolic differences between the two groups. These findings indicate metabolic alterations across multiple pathways in BTC.

Conclusions: Paired tissue metabolomics revealed coordinated metabolic alterations in BTC involving choline phospholipid precursor metabolism, amino sugar and nucleotide sugar metabolism, and additional amino acid-related pathways. These results highlight the presence of broad metabolic reprogramming in BTC and underscore the importance of tissue-based metabolomic profiling for characterizing tumor metabolism.

Keywords: Amino acid metabolism; Biliary tract cancer; Choline phospholipid precursor metabolism; Metabolomics; Pathway analysis.

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The cellular stress sensor HSPB1 regulates the membrane localization of amino acid transporter SLC7A5 in breast cancer

Suzuki, Y., Kitayama, N., Kudo, R., Silwal, K., Matsuda, S., Ohishi, M., Ueno, A., Ashitani, S., Igarashi K., Masuda, T., Ishikawa, T., Soga T., Saito, Y.

J. Biol. Chem. 302 ( 7 ) 113197 2026.06

Research paper (scientific journal), Joint Work, Accepted, ISSN 00219258

The heat shock protein beta-1 (HSPB1/HSP27) is highly expressed and phosphorylated in cancer tissues. However, the precise role of HSPB1 in cancer remains unclear. In this study, we report the unexpected findings elucidating the essential role of HSPB1 in adapting amino acid deficiency by upregulating amino acid transporter SLC7A5 function. HSPB1 regulates estrogen receptor-positive (ER+) breast cancer cell proliferation in a SLC7A5-dependent manner. In response to cellular stress, which is specified as amino acid-deficient conditions, HSPB1 was phosphorylated at Ser 78 residue by stress MAPK p38. SLC7A5 is associated with phosphorylated HSPB1 for its functional activation, leading to upregulated amino acid incorporation. In addition, HSPB1 and SLC7A5 overexpression increased acetylated α-tubulin levels. SLC7A5 overexpression did not change acetyl-CoA level, but SLC7A5 knockdown decreased ATAT1 and induced HDAC6 upregulation. Furthermore, HSPB1 and SLC7A5 induced paclitaxel and tamoxifen resistance. Therefore, the HSPB1-SLC7A5 axis contributes to the acquisition of tolerance to both tamoxifen and paclitaxel in breast cancer cells, uncovering a novel therapeutic target against drug resistance in breast cancer.

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An enrichment-based approach to interpreting metabolomic data using differential metabolomic profiles within the iDMET framework

Matsuta, R., Yamamoto, H., Fukushima, A., Tabata, S., Makinoshima, H., Soga, T., Saito, R., Hyakawa, E.

BMC Bioinformatics 27 ( 1 ) 131 - 131 2026.06

Research paper (scientific journal), Joint Work, Accepted

BACKGROUND: Pathway enrichment analysis is a crucial method for the biological interpretation of metabolomic data by identifying associations between altered metabolites and biological pathways. However, such traditional approaches often rely on a limited set of predefined metabolic pathways, resulting in a low likelihood of discovering pathways associated with a given metabolic profile. To overcome this limitation, we extended our previously developed iDMET methodology to incorporate a broader range of metabolite sets, including those derived from differential metabolomic profiles. This enhanced approach, termed iDMET+, significantly expands dataset diversity and size, increasing the likelihood of discovering associated metabolite sets for a given metabolic profile, thereby enables more biological insights to be obtained from the metabolic profile. RESULTS: We validated iDMET+ through case studies on three diseases: clear cell renal cell carcinoma, colorectal cancer, and small cell lung cancer. First, using a clear cell renal cell carcinoma study as input, iDMET+ correctly identified another study of the same disease that involved metabolomic analysis. This pair of studies was identified as relevant in our previous iDMET results, showing the consistency between iDMET+ and iDMET. Second, using the metabolomic profile of colorectal cancer as input, iDMET+ identified not only another metabolomic study of the same cancer but, surprisingly, also metabolomic studies on prostate cancer and a high-fat diet. These studies focused on MYC-driven metabolic reprogramming, which was also a major focus of the input study. In both case studies, related studies were enriched because the differential metabolomic profiles of directly associated studies were part of the metabolite set. In contrast, the small cell lung cancer study highlighted limitations in dataset coverage—the absence of directly relevant differential metabolomic profiles resulted in fewer enriched metabolite sets. Nevertheless, the analysis of commonly altered metabolites still yielded some meaningful results. Metabolite alterations associated with inhibition of the purine salvage pathway were observed, suggesting potential involvement in tumor metabolic reprogramming. CONCLUSIONS: These results demonstrate that iDMET+ offers broader biologically relevant information than the conventional pathway-based approaches and has the potential to uncover biologically significant findings by searching across diverse datasets. This work also identifies areas of improvements for iDMET+.

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Optimization of lens size and ion source parameters for gas chromatography/mass spectrometry-based metabolomics using hydrogen as a carrier gas

Sato, M., Hayasaka, R., Soga, T., Hirayama, A.

J. Chromatogr. A 1776 466945 2026.06

Research paper (scientific journal), Joint Work, Accepted

Gas chromatography/mass spectrometry (GC/MS) is widely employed in metabolomics owing to its high resolution, reproducibility, and compatibility with volatile and semi-volatile compounds. While helium has traditionally been used as the carrier gas, increasing costs and global shortages have prompted the exploration of hydrogen gas as an alternative. Hydrogen offers faster analysis times and reduced ion source contamination but presents challenges, including ion source reactions, which can change compound fragmentation patterns. To address this, a hydrogen-deactivated electron ionization (EI) source has been developed to minimize undesired chemical interactions and improve spectral integrity. In this study, we systematically evaluated the effect of extraction lens sizes (3, 6, and 9 mm) under hydrogen carrier gas conditions using n-alkane and human metabolomic standard solutions. The hydrogen-deactivated ion source equipped with a 3 mm extraction lens provided superior peak symmetry and the highest signal intensities, with acceptable relative standard deviation (RSD) values (i.e., below 30%). In addition, the reproducible fragmentation patterns as those observed with helium carrier gas were obtained for phosphorylated metabolites. Using this optimized configuration, we applied hydrogen gas-based GC/MS to metabolomic profiling of the human colon cancer cell line HCT116 with mutant isocitrate dehydrogenase 1 (IDH1). Key metabolic alterations, including increased levels of the known biomarker 2-hydroxyglutaric acid, were detected in IDH1-mutant cells compared with wild-type cells. These findings establish hydrogen gas-based GC/MS with a hydrogen-deactivated ion source as a robust and reliable platform for metabolomics, offering an effective alternative to helium-based systems.

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Polypharmacologic phosphoinositide modulation by FTY720 triggers endomembrane trafficking collapse and metabolic starvation in cancer cells

Kofuji, S., Sumita, K., Ikeda, Y., Takahashi, Y., Tabata, S., Ito, D., Hirota, Y., Sasaki, M., Kanoh, H., Nakatsu, F., Takeuchi, K., Senda, T., Davis, M.I. Shen, M., Wakimoto, H., Hirayama, A., Soga, T., Simeonov, A., Sasaki, A.T.

Biochem. Biophys. Res. Commun. 815 153671 2026.05

Research paper (scientific journal), Joint Work, Accepted

Phosphoinositides coordinate membrane trafficking and bioenergetic homeostasis, and many tumors rely on elevated phosphoinositide flux to sustain growth. Therapeutic development has largely pursued single-phosphoinositide kinase inhibition, whereas polypharmacologic strategies that perturb the broader network remain underexplored. FTY720 (fingolimod), a clinically approved sphingosine-1-phosphate receptor modulator, shows anti-tumor activity at micromolar concentrations, but its non-canonical mechanisms remain incompletely defined. Building on our work with the structurally related compound KRP203, we show that high-dose FTY720 produces isozyme-divergent modulation across phosphoinositide kinases and biases PIKFYVE activity toward phosphatidylinositol, a pattern we term ASURA (Asymmetric Simultaneous Uncoupling of Related Activities). FTY720 induces vacuolization and endomembrane remodeling in cancer cells, and suppresses macropinocytic ruffling as demonstrated by tracer uptake and scanning ion conductance microscopy analyses. Quantitative metabolomics revealed depletion of intracellular amino acids and ribonucleoside triphosphates, coupled with reduced glycolysis. Concurrently, FTY720 induced extensive rewiring of the hexosamine pathway, nitrogen metabolism, and tricarboxylic acid (TCA)-cycle anaplerosis, along with redox signatures indicating oxidative stress despite a nutrient-replete medium. The metabolites depleted by FTY720 showed extensive, directionally concordant overlap with those depleted by PTEN induction. Patient-derived glioblastoma (GBM) neurospheres were sensitive to FTY720, and co-treatment with a PI3Kα-selective inhibitor augmented growth suppression in U87MG cells. Together, these data support a model in which ASURA-dose FTY720 disrupts phosphoinositide-regulated trafficking and nutrient access, imposing intracellular nutrient stress that culminates in tumor-cell death.

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Longitudinal study of plasma metabolites during menopause and their associations with later onset of metabolic syndrome

Miyake, A., Iida, M., Harada, S., Sugiyama, D., Matsumoto, M., Miyagawa, N., Toki, R., Edagawa, S., Hirata, A., Kuwabara, K., Okamura, T., Sato, A., Amano, K., Hirayama, A., Sugimoto, M., Soga, T., Tomita, M., Arakawa, K., Kisu, I., Yamagami, W., Takebayashi, T.

J. Clin. Endocrinol. Metab. 111 ( 6 ) e1672 - e1680 2026.05

Research paper (scientific journal), Joint Work, Accepted, ISSN 0021972X

Context: Previous metabolomics studies suggest potential associations between menopausal changes in lipids and an increased risk of metabolic syndrome (MetS). However, longitudinal data on other key metabolites, such as branched-chain amino acids and homocysteine, remain limited, and most studies lack long-term follow-up across the menopause transition.

Objective: This study aimed to investigate longitudinal changes in circulating metabolites during menopause over a mean follow-up of 5 years and assess their associations with subsequent MetS development.

Methods: Premenopausal women from the Tsuruoka Metabolomics Cohort Study who participated in at least one follow-up survey were included. Menopausal status, data on MetS, and plasma metabolites profiled using capillary electrophoresis mass spectrometry were assessed at each visit. Thirty-one metabolites were examined for associations with menopausal status using mixed-effects models. The association of these menopause-related metabolites with MetS development was examined via logistic regression analysis adjusted for follow-up duration.

Results: Among 953 women (43.8 ± 5.4 years old), 316 (33.2%) reached menopause during follow-up (5.0 ± 1.1 years). Eighteen metabolites changed significantly with menopause, particularly those related to BCAA metabolism, urea cycle, and homocysteine metabolism. Of 695 women without MetS at baseline, 65 (9.4%) developed MetS. Glutamate (odds ratio [95% confidence interval]: 1.95 [1.49-2.57]) was associated with higher MetS risk. Higher levels of glutamate, valine, leucine, and cystine were significantly associated with the development of hyperglycemia.

Conclusions: Longitudinal changes in charged metabolites occur across the menopausal transition, with specific metabolites such as glutamate possibly contributing to the metabolic alterations underlying increased MetS risk.

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Global loss of metabolic responsiveness and elevated enzyme in leptin deficient obese mice during starvation

Li, D., Morita, K., Kokaji, T., Hatano, A., Hirayama, A., Soga, T., Suzuki, Y., Matsumoto, M., Tsuchiya, T., Ozaki, H., Ohno, S., Inoue, H., Inaba, Y., Sugimoto, H., Pan, Y., Kuroda, S.

npj Syst. Biol. Appl. 12 ( 1 ) 53 - 53 2026.03

Research paper (scientific journal), Joint Work, Accepted

Starvation induces complex metabolic adaptations in skeletal muscle, a key tissue for maintaining energy homeostasis; however, these adaptations are largely impaired in obesity. How obesity alters global metabolic adaptations to starvation in skeletal muscle remains unclear. Here, we analyzed the metabolic adaptations on a trans-omics scale during starvation in skeletal muscle from wild-type (WT) and leptin-deficient obese (ob/ob) mice. We measured multi-omics data during starvation and constructed global trans-omics networks in WT and ob/ob mice. We found that starvation induces “responsiveness” in WT mice, characterized by increases or decreases in key regulator metabolites, including ATP and AMP, as well as enzyme proteins, leading to global regulation of metabolic pathways, which was lost in ob/ob mice. In contrast, during starvation, ob/ob mice exhibit “difference” in comparison to WT mice, manifested by the persistently elevated expression of metabolic enzymes. These features were similarly found in liver, another key metabolic organ. Thus, global loss of responsiveness and elevated enzyme proteins are systemic features of metabolic dysregulation in ob/ob mice.

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Guanine nucleotides drive ribosome biogenesis and glycolytic reprogramming in acute myeloid leukemia stem cells

Kawano, G., Ikeda, R., Ishihara, D., Shima, T., Sakoda, T., Yamamoto, S., Kochi, Y., Semba, Y., Ashitani, S., Mori, Y., Kato K., Maeda, T., Miyamoto, T., Soga, T., Akashi, K., Kikushige, Y.

Blood 147 ( 7 ) 768 - 782 2026.02

Research paper (scientific journal), Joint Work, Accepted, ISSN 00064971

Therapy resistance in acute myeloid leukemia (AML) remains a major clinical obstacle, particularly due to the persistence of leukemia stem cells (LSCs) capable of metabolic adaptation. While venetoclax (Ven) inhibits oxidative phosphorylation (OXPHOS), we found that Ven-resistant LSCs undergo glycolytic reprogramming to bypass OXPHOS inhibition. This metabolic shift is supported by enhanced ribosome biogenesis, sustained by upregulated de novo guanine nucleotide biosynthesis. Abundant guanine nucleotides suppress the impaired ribosome biogenesis checkpoint (IRBC), leading to TP53 destabilization and persistent MYC expression. Inhibition of inosine monophosphate dehydrogenases (IMPDH1/2) depletes guanine nucleotides, activates IRBC, stabilizes TP53, represses MYC, and impairs the metabolic shift to glycolysis. This metabolic rewiring disrupts LSC stemness and suppresses the reconstitution of human AML cells in xenotransplantation experiments. Notably, the suppression of LSC stemness was observed regardless of Ven resistance or the TP53 mutational status of AML cells. These findings reveal that mutation-independent TP53 inactivation is involved in resistant AML and suggest that targeting guanine nucleotide biosynthesis may offer a clinically actionable strategy to eradicate therapy-resistant LSCs.

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Cross-sectional associations between CES-D scores and the salivary metabolome in nonclinical adults

Kubo, Y., Yamauchi, F., Goshima, N., Ohishi, M., Hasegawa, T., Soga, T., Ikeda, M., Aoki, K.

Discov. Ment. Heatlh 6 ( 1 ) 15 - 15 2026.01

Research paper (scientific journal), Joint Work, Accepted

Background: Depression represents a major global disease burden. While the Center for Epidemiologic Studies Depression Scale (CES-D) is widely used, it relies on subjective self-reporting. Saliva enables non-invasive metabolite analysis, but existing metabolomics studies have focused on clinical depression using blood or urine, with limited investigation of salivary metabolites in community populations. This study investigated associations between CES-D scores and salivary metabolite concentrations in Tokyo residents.

Methods: This cross-sectional study collected CES-D responses and morning saliva samples from Tokyo residents. Salivary metabolites were analyzed using capillary electrophoresis time-of-flight mass spectrometry. Statistical analyses included permutational multivariate analysis of variance (PERMANOVA) for overall metabolite-CES-D associations, pathway enrichment analysis using fast gene set enrichment analysis (FGSEA), and principal component analysis, adjusted for age and sex.

Results: Analysis included 107 participants (40 males, 67 females; mean age 55.3 ± 14.2 years). PERMANOVA revealed significant association between 112 salivary metabolites and CES-D scores (F = 2.870, p = 0.003), with metabolites explaining 7.7% of depressive symptom variance. Pathway enrichment analysis identified significant alterations in amino acid metabolism (normalized enrichment score =-1.750, q = 0.007). Glycolysis and amine/polyamine metabolism showed trend-level enrichment (both q = 0.066). Principal component analysis revealed significant correlations between CES-D scores and pathway activity for amino acid metabolism (r = 0.216, p = 0.027) and amine/polyamine metabolism (r = 0.216, p = 0.027).

Conclusion: This study demonstrates significant associations between salivary metabolite profiles and depressive symptoms in a nonclinical community population, with amino acid metabolism emerging as the most robustly altered pathway. These findings provide preliminary evidence for associations between salivary metabolomic profiles and depressive symptoms in a nonclinical community population.

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Abrogation of aberrant glycolytic interactions eliminates senescent cells and alleviates aging-related dysfunctions

Mikawa, T., Kameda, M., Ikari, S., Shibata, E., Liu, S., Miyagawa, S., Ono, K., Ito, T., Yoshizawa, A., Sugimoto, M., Shibuya, S., Shimizu, T., Almunia, J., Ogiso, N., Revêchon, G., Palazzo, A., Bernard, D., Kanda, H., Soga, T., Takubo, K., Morioka, S., Sasaki, J., Sasaki, T., Itamoto, A., Fujii, T., Seno, H., Inagaki, N., Kondoh, H.

Signal Transduct. Target. Ther. 10 ( 1 ) 402 - 402 2025.12

Research paper (scientific journal), Joint Work, Accepted, ISSN 20959907

Cellular senescence is deeply involved in physiological homeostasis, development, tissue repair, aging, and diseases. Senescent cells (SnCs) accumulate in aged tissues and exert deleterious effects by secreting proinflammatory molecules that contribute to chronic inflammation and aging-related diseases. We revealed that an aberrant interaction between glycolytic PGAM1 and Chk1 kinase is augmented in SnCs associated with increased glycolysis, whose byproduct, lactate, promotes this binding in a noncell autonomous manner. The pseudo-Warburg effect of SnCs with enhanced PPP (pentose phosphate pathway) activity is maintained by HIF-2α phosphorylation by Chk1 and subsequent upregulation of glycolytic enzymes, creating a vicious cycle reprogramming the glycolytic pathway in SnCs. HIF-2α also activates FoxM1 expression, which transcriptionally suppresses proapoptotic profiles, including BIM, and upregulates DNA repair machineries in SnCs. FoxM1 thus supports the genomic integrity and survival capacity of SnCs during their glycolytic changes. Chemical abrogation of PGAM1-Chk1 binding reverts these phenotypes and eliminates SnCs through senolysis. Inhibition of the PGAM1-Chk1 interaction improves physiological parameters during aging and inhibits lung fibrosis in mouse models. Our study highlights a novel pathway contributing to the metabolic reprogramming of SnCs and how the use of a new senolytic molecule that targets the PGAM-Chk1 interaction creates a specific vulnerability of those cells to potentially fight age-related diseases.

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Context-specific metabolic alterations in HPRT1 knockout cells within a 3D culture system

Tabata, S., Fujimoto, I., Soga, T., Makinoshima, H.

Cancer Med. 14 ( 23 ) e71452 - e71452 2025.12

Research paper (scientific journal), Joint Work, Accepted

Background: Cancer cells reprogram their metabolism to sustain energy production and biosynthesis for malignant proliferation; however, their metabolic phenotypes vary significantly across different growth environments, creating discrepancies between in vitro and in vivo findings. These inconsistencies pose challenges for translating metabolic research into clinical applications. The emergence of 3D culture models as in vitro systems that accurately mimic the in vivo environment can mitigate these challenges by providing conditions that reflect physiological architecture and metabolic interactions. Therefore, we investigated the impact of the purine metabolism enzyme hypoxanthine-guanine phosphoribosyltransferase 1 (HPRT1) on the proliferation and metabolism of SCLC cells using 2D and 3D culture models, with the goal of identifying context-specific metabolic regulation not captured in conventional 2D cultures.

Methods: We evaluated cell proliferation and performed metabolomic profiling of HPRT1-knockout (KO) SCLC cells grown in 2D cultures, two 3D culture systems, and mouse xenograft models. Metabolomic profiling was performed using CE-TOFMS, followed by PCA and pathway analysis. The expression of β-alanine (β-Ala) metabolism-related genes, including carnosine synthase 1 (CARNS1), was assessed by RNA-seq and RT-PCR. CARNS1 expression was further evaluated in publicly available lung cancer datasets, including both cell line and clinical tumor cohorts, to determine its association with patient prognosis and its correlation with HPRT1 expression.

Results: The knockout of HPRT1 significantly reduced cell proliferation in 3D cultures and in vivo but had a minimal impact in 2D cultures. Comprehensive metabolomic analyses of HPRT1-KO cells revealed extensive alterations in amino acid and purine metabolism both in vitro and in vivo. Notably, the effect of HPRT1 KO on β-Ala metabolism differed between 2D and 3D cultures. In 3D cultures, HPRT1 KO led to increased expression of the endogenous antitumor metabolite carnosine and its biosynthetic enzyme CARNS1 within the β-Ala metabolic pathway. Furthermore, analysis of clinical databases showed that high CARNS1 expression correlated with improved prognosis in patients with lung cancer and negatively correlated with HPRT1 expression in tumor tissues.

Conclusion: This study highlights the potential of 3D culture systems to elucidate context-specific mechanisms of metabolic regulation, such as the suppressive effect of HPRT1 on carnosine production. Our findings demonstrate that metabolic phenotypes observed in 2D cultures may not fully capture the complexity of in vivo metabolism, whereas 3D models can reveal regulatory pathways that are otherwise overlooked, including context-dependent regulation of carnosine metabolism by HPRT1.

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Decreased Fecal Nicotinamide and Increased Bacterial Nicotinamidase Gene Expression in Ulcerative Colitis Patients

Aoyama, K., Yamamura, R., Katsurada, T., Shimizu, T., Takahashi, D., Kondo, E., Iwasaki, N., Tamakoshi, A., Soga, T., Fukuda, S., Sonoshita, M., Sakamoto, N.

Inflamm. Bowel Dis. 31 ( 10 ) 2815 - 2825 2025.10

Research paper (scientific journal), Joint Work, Accepted, ISSN 10780998

Background/objective: Ulcerative colitis (UC) is significantly linked with gut microbiota, which is essential for maintaining gut health. Their metabolites mitigate gut inflammation and bolster barrier function. Among these metabolites, we focused on vitamin B3, which has been reported to improve the pathogenesis of UC in mice. This study aimed to compare fecal vitamin B3 and gut microbiota between non-UC and UC patients.

Methods: We assessed fecal metabolites and gut microbiota in 71 UC patients (UC group) and 72 non-UC patients (non-UC group) matched by sex and age in 10-year intervals. Fecal samples were collected and metabolites were analyzed using capillary electrophoresis time-of-flight mass spectrometry. Bacterial DNA was extracted for 16S rRNA gene sequencing. We analyzed fecal nicotinamide levels and gut microbiota composition, employing statistical adjustments for confounding factors.

Results: We found that the UC group exhibited significantly lower fecal nicotinamide levels and α-diversity (Shannon index) compared to the non-UC group. The relative abundance of bacterial genera such as Treponema, UCG-002, and Fusicatenibacter was decreased, while Sellimonas, Fournierella, and Oscillospira were increased in the UC group. Moreover, a negative correlation was observed between Sellimonas abundance and fecal nicotinamide levels in the UC group. Additionally, the UC group showed higher expression of a bacterial gene encoding nicotinamidase compared to the non-UC group.

Conclusions: These findings suggest that gut microbiota dysbiosis contributes to reduced vitamin B3 metabolism in UC patients. The study highlights the potential of replenishing vitamin B3 metabolic pathways as a novel therapeutic approach for UC treatment.

Keywords: gut microbiota; inflammatory bowel disease; nicotinamide; ulcerative colitis; vitamin B3.

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Dysregulated Anaerobic Glycolysis in Podocytes is Relevant to the Progression of Focal Segmental Glomerulosclerosis

Sugimura, M., Maeda, K., Shibata, K., Seko, H., Kozaki, Y., Hirayama, A., Soga, T., Ozeki, T., Sato, Y., Kato, N., Kosugi, T., Kadomatsu, K., Maruyama, S.

Kidney Int. Rep. 10 ( 9 ) 3239 - 3254 2025.09

Research paper (scientific journal), Joint Work, Accepted

Introduction
Minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are podocytopathies with varying clinical courses and therapeutic responses. FSGS often leads to end-stage renal disease. Consequently, their heterogeneity requires case stratification and pathophysiological elucidation. The involvement of energy metabolism in FSGS pathogenesis and stratification has not been clarified. Therefore, this study aimed to verify whether evaluating energy kinetics can be a new approach to MCD or FSGS stratification and explore the role of energy metabolism in MCD or FSGS.
Methods
Cultured human podocytes were treated with sera from patients with biopsy-confirmed MCD or FSGS. Serum-treated podocytes were analyzed for apoptosis using flow cytometry, metabolomics via mass spectrometry, and real-time adenosine triphosphate (ATP) production rates using an extracellular flux analyzer. Adriamycin-induced nephropathy was induced in podocyte-specific lactate dehydrogenase (LDH) A (LDHA)-deficient and control mice.
Results
The sera from patients with FSGS significantly induced apoptosis in human podocytes compared with those from individuals with MCD. Apoptosis severity was associated with segmental obliteration and corticosteroid resistance. Metabolomic analysis revealed differences in anaerobic glycolysis and tricarboxylic acid cycle (TCA)-related metabolites in podocytes exposed to the sera of patients with MCD and FSGS. In the podocytes treated with sera from patients with FSGS, glycolytic ATP production significantly decreased in cases with high apoptosis rates. The sera from patients with FSGS suppressed LDHA activity, suppressed α-actinin 4 (ACTN4) expression, and promoted actin remodeling of podocytes. Segmental sclerosis was more prominent in podocyte-specific LDHA-deficient mice with adriamycin-induced nephropathy than in control mice.
Conclusion
FSGS progression was associated with decreased anaerobic glycolysis in podocytes.

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EML4–ALK Rearrangement Creates a Distinctive Myeloid Cell–Dominant Immunosuppressive Microenvironment in Lung Cancer

Arai, K., Nishito, Y., Mizuno, H., Motoi, N., Hiraoka, N., Fuse, M., Arai, Y., Shibata, T., Sonobe, Y., Kayukawa, Y., Maruyama, T., Fukuda, H., Mizoguchi, Y., Aikawa, Y., Yoshida, Y., Watanabe, S., Sakamoto, H., Yamashita, M., Kitano, S., Nagata, Y., Mitsumori, R., Ozaki, K., Niida, S., Kanai, Y., Hirayama, A., Soga, T., Yoshida, T., Yasuda, K., Ochiai, A., Tsunoda, H., Aoki, K.

Cancer Immunol. Res. 13 ( 9 ) 1435 - 1452 2025.09

Research paper (scientific journal), Joint Work, ISSN 23266066

Tyrosine kinase inhibitors are initially efficacious against anaplastic lymphoma kinase (ALK) fusion gene-positive lung adenocarcinoma, but acquired resistance inevitably occurs. Therefore, alternative treatment strategies are needed for tyrosine kinase inhibitor-resistant cases. Although the use of immune checkpoint inhibitors (ICI) has improved the prognosis of patients with lung cancer, patients with ALK+ lung adenocarcinoma exhibit little or no response to immunotherapy and the underlying resistance mechanisms remain unknown. In this study, we explored the immunologic status of the tumor microenvironment (TME) in ALK+ lung adenocarcinoma tissues. Tumor-infiltrating leukocyte analysis revealed reduced numbers of effector T cells and increased myeloid-derived suppressor cells (MDSC) relative to ALK- lung adenocarcinoma cases, indicating that ALK+ lung adenocarcinoma has a myeloid cell-dominant immunosuppressive TME. Single-cell RNA sequencing analysis identified a subset of macrophages that expressed most T cell-attractant chemokines (CXCL9, CXCL10, and CXCL11), and the macrophages were inactivated in ALK+ lung adenocarcinoma. In contrast, ALK+ lung adenocarcinoma expressed high levels of MDSC-attractant chemokines (CXCL1 and CXCL8). In addition, ALK+ lung adenocarcinoma showed higher levels of IL6, an MDSC-inducing cytokine, than ALK- lung adenocarcinoma. An IL6R inhibitor transformed the TME in a murine ALK+ lung adenocarcinoma model, shifting it from an immunosuppressive to a T cell-dominant status. Although ICI monotherapy lacked antitumor effects, a combination of ICI and the IL6R inhibitor had significant antitumor effects in mice. Our findings illustrate the molecular basis of fusion gene-mediated immunosuppressive TMEs, providing a rationale for a novel combination immunotherapy for ALK+ lung adenocarcinoma. See related Spotlight by Vitale and Bria, p.1326.

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Lubiprostone in chronic kidney disease: Insights into mitochondrial function and polyamines from a randomized phase 2 clinical trial

Watanabe, S., Nakayama, M., Yokoo, T., Sanada, S., Ubara, Y., Komatsuda, A., Asanuma, K., Suzuki, Y., Konta, T., Kazama, J. J., Suzuki, T., Fukuda, S., Soga, T., Yamada, T., Mizutani, S., Matsumoto, M., Naito, Y., Taguchi, K., Fukami, K., Kashiwagi, H., Kikuchi, K., Suzuki, C., Tokuno, H., Urasato, M., Kujirai, R., Matsumoto, Y., Akiyama, Y., Tomioka, Y., Itai, S., Tongu, Y., Mishima, E., Kawabe, C., Kasahara, T., Ogata, Y., Toyohara, T., Sato, T., Tanaka, T., Abe, T., LUBI-CKD TRIAL Investigators

Sci. Adv. 11 ( 35 ) eadw3934 2025.08

Research paper (scientific journal), Accepted

Chronic kidney disease (CKD) is a life-threatening condition, and constipation is a progressive risk factor. We evaluated changes in uremic toxins, renal function, and the safety of lubiprostone, a selective chloride channel activator, in patients with CKD. In this phase 2, randomized, double-blind, placebo-controlled trial across nine centers in Japan, 150 patients with stage IIIb-IV CKD received lubiprostone (8 or 16 micrograms) or placebo for 24 weeks. The primary end point was change in indoxyl sulfate levels. Secondary end points included other uremic toxins and renal function markers. Lubiprostone did not alter uremic toxin levels but improved or preserved estimated glomerular filtration rate and its slope in the 16-microgram group. Mild-to-moderate gastrointestinal events occurred in the placebo and 16-microgram groups. Multiomics analysis revealed that lubiprostone modulated the gut microbial agmatine pathway and increased spermidine levels, thereby improving renal mitochondrial function. Lubiprostone is a previously unknown and safe therapeutic option to mitigate renal decline in CKD.

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