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 2026.03

Joint Work, Accepted

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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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. online 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

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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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. online dgaf666 2025.12

Research paper (scientific journal), Joint Work, Accepted

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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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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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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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 online 1 - 15 2025.08

Research paper (scientific journal), 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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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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