bims-glucam 2025-06-22 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2025–06–22
fourteen papers selected by
Sreeparna Banerjee, Middle East Technical University

The Long Run: A Tribute to Arthur Joseph Lawrence Cooper.
Targeting glutamine metabolism in CD4+ T-cell-mediated autoimmune diseases.
The RNA demethylase FTO promotes glutamine metabolism in clear cell renal cell carcinoma through the regulation of SLC1A5.
Targeting amino acid in tumor therapy.
Circular RNA-Sirt1 sponges miR-27b-3p to protect vascular smooth muscle cell injury during atherosclerosis through regulating the glutamine metabolism pathway.
GSTP1 knockdown induces metabolic changes affecting energy production and lipid balance in pancreatic cancer cells.
Uncovering metabolic pathways in human alveolar macrophages in response to lipopolysaccharide.
Iron deficiency causes aspartate-sensitive dysfunction in CD8+ T cells.
Proteomic and metabolomic analysis of platelet related samples reveals energy metabolism disorders in hepatocellular carcinoma.
The crucial role of metabolic reprogramming in driving macrophage conversion in kidney disease.
Fructose Metabolism in Cancer: Molecular Mechanisms and Therapeutic Implications.
D-mannose augments targeted radioligand-immunotherapy of prostate cancer by enhancing radiosensitivity and reshaping immune microenvironment.
The STAT3-VDAC1 axis modulates mitochondrial function and plays a critical role in the survival of acute myeloid leukemia cells.
Untargeted metabolomics reveals the inhibition effect of a high-fat diet on colorectal cancer tumorigenesis in obesity-resistant mice via regulating bile acid, glutathione, and glycerophospholipid metabolisms.

Anal Biochem. 2025 Jun 18. pii: S0003-2697(25)00165-4. [Epub ahead of print] 115926

The Long Run: A Tribute to Arthur Joseph Lawrence Cooper.

John T Pinto, Thambi Dorai, Thomas M Jeitner, Travis T Denton.

In this issue of Analytical Biochemistry, we honor the life and legacy of Arthur Joseph Lawrence Cooper (1946-2024). Born in London, Arthur made pioneering contributions to medical science, particularly in understanding the role of glutamine in the brain and cancer cell metabolism. His research revealed how glutamine supports neurotransmitter synthesis, energy production, and ammonia detoxification, as well as its critical role in cancer cell growth. His work has greatly advanced both neuroscience and cancer biology, offering insights that could lead to new therapeutic strategies targeting glutamine metabolism.

DOI: https://doi.org/10.1016/j.ab.2025.115926
Immunol Cell Biol. 2025 Jun 18.

Targeting glutamine metabolism in CD4+ T-cell-mediated autoimmune diseases.

Zheng Li, ZeHong Su, ZhiMin Wu, LvHeng He, PingPing Hu, GaoJian Lian.

  CD4+ T cells play a vital role in the occurrence and development of autoimmune diseases (AID). The differentiation direction and function of CD4+ T cells are both regulated by metabolic reprogramming, which differs across various CD4+ T subsets. Glutamine (Gln), as an immunoregulatory nutrient, not only provides bioenergy and biosynthesis for the differentiation and effector function of CD4+ T cells but also regulates intracellular redox conditions and produces metabolic intermediates that are used for epigenetic modification of effector cell genes. Here, we review the metabolic characteristics of Gln in CD4+ T cells and its regulatory effects on CD4+ T-cell differentiation and function. We also summarize potential targets on Gln metabolism for AID therapy, including Gln transporters, Gls1, GSH synthesis and epigenetic modification. However, the primary challenge remains how to achieve cell type-specific metabolic inhibition in vivo. Therefore, future research should focus on developing selective and effective therapeutic agents that modulate Gln metabolism while minimizing cytotoxicity for AID treatment.

Keywords:  autoimmune disease; epigenetic modification; glutamine; glutaminolysis; selective immunotherapy

DOI:  https://doi.org/10.1111/imcb.70042
Sci Adv. 2025 Jun 20. 11(25): eadv2417

The RNA demethylase FTO promotes glutamine metabolism in clear cell renal cell carcinoma through the regulation of SLC1A5.

Man Zhao, Dalin Zhang, Haowen Jiang, Nishanth Kuganesan, Suchitra Natarajan, Leighton Pu, Kaushik N Thakkar, Hongjuan Zhao, Quynh Thu Le, Amato J Giaccia, James D Brooks, Donna M Peehl, Jiangbin Ye, Erinn B Rankin.

Glutamine reprogramming plays a crucial role in the growth and survival of clear cell renal cell carcinoma (ccRCC), although the mechanisms governing its regulation are still not fully understood. We demonstrate that the RNA demethylase fat mass and obesity-associated gene (FTO) drives glutamine reprogramming to support ccRCC growth and survival. Genetic and pharmacologic inhibition of FTO in ccRCC cells impaired glutamine-derived reductive carboxylation, depleted pyrimidines, and increased reactive oxygen species. This led to increased DNA damage and reduced survival, which could be rescued by pyrimidine nucleobases or the antioxidant N-acetylcysteine. Mechanistically, FTO demethylates the glutamine transporter solute carrier family 1 member 5 (SLC1A5) messenger RNA to promote its expression. Restoration of SLC1A5 expression in FTO-knockdown cells rescued metabolic and survival defects. FTO inhibition reduced ccRCC tumor xenograft and PDX growth under the renal capsule. Our findings indicate that FTO is an epitranscriptomic regulator of ccRCC glutamine reprogramming and highlight the therapeutic potential of targeting FTO for the treatment of ccRCC.

DOI: https://doi.org/10.1126/sciadv.adv2417
Front Oncol. 2025 ;15 1582116

Targeting amino acid in tumor therapy.

Mingpai Ge, Yuan Xu, Lu Cui, Enyuan Huang, Zhaorui Liu, Kai Yin.

  Tumor cells undergo profound metabolic reprogramming to sustain their rapid growth and proliferation, with amino acids serving as essential nutrients critical for protein synthesis, energy metabolism, nucleotide production, and redox balance. The increased reliance of tumor cells on specific amino acids represents a promising therapeutic target. This review provides an in-depth analysis of the biological roles of amino acids in cancer, identifies vulnerabilities associated with amino acid dependency, and discusses strategies to leverage these weaknesses for enhanced cancer treatment. We explore the mechanisms governing amino acid uptake, utilization, and metabolism in tumor cells, as well as their interactions with the tumor microenvironment. Additionally, the review addresses the challenges and prospects of targeting amino acid metabolism in cancer therapy, including issues of resistance, the complexity of metabolic pathways, and the potential for personalized treatment approaches.

Keywords:  amino acid; amino acid metabolism; cancer metabolism; cancer therapy; metabolism

DOI:  https://doi.org/10.3389/fonc.2025.1582116
Cytotechnology. 2025 Aug;77(4): 122

Circular RNA-Sirt1 sponges miR-27b-3p to protect vascular smooth muscle cell injury during atherosclerosis through regulating the glutamine metabolism pathway.

Qian Song, Xiang Wang, Qinghua Zeng, Hui Xu, Lin Liu.

  Atherosclerosis is a progressive pathological disorder resulting in various vital cardiovascular diseases such as myocardial infarction and stroke, leading to high mortality worldwide. Currently, the precise mechanisms of pathogenesis and progression of atherosclerosis remained unclear. Circular RNAs (circRNAs) have been implicated in vital processes of cardiovascular disease. In this study, we aimed to investigate the roles of circSirt1 in vascular smooth muscle cell (VSMC) injury during atherosclerosis. We found circSirt1 was significantly downregulated in VSMCs from atherosclerosis patients compared with those from healthy controls. Under oxidative stress, expression of circSirt1 was remarkedly suppressed in VSMCs. Notably, overexpression of circSirt1 effectively protected the oxidative stress-induced VSMC injury. On the other way, miRNA-27b-3p was high-expressed in VSMCs from atherosclerosis patients and was effectively induced under oxidative stress. Overexpression of miR-27b-3p exacerbated the oxidative stress-induced VSMC injury. From the non-coding RNA service, starBase, circSirt1 was predicted to interact with miR-27b-3p. This association was further validated by RNA pull-down and luciferase assays. We detected glutamine metabolism rate was depressed under oxidative stress and low glutamine supply rendered VSMCs more susceptible to oxidative stress. Furthermore, we identified the glutamine metabolism key enzyme, glutaminase (GLS) as a direct target of miR-27b-3p in VSMCs. miR-27b-3p blocked glutamine metabolism and promoted VSMC cell injury through direct targeting GLS. Finally, rescue experiments verified the circSirt1-protected VSMC injury was through regulating the miR-27b-3p-GLS axis that restoration of miR-27b-3p in circSirt1-overexpressed VSMCs successfully overrode the high-circSirt1-moduated miR-27b-3p and GLS expressions and the oxidative stress-induced VSMC injury. Summarily, these results unveiled vital roles and molecular mechanisms of circSirt1 in oxidative stress-induced VSMC injury during atherosclerosis by regulating the miR-27b-3p-GLS axis, indicating rescue of circSirt1 in VSMCs could be an effectively therapeutic approach to treat atherosclerosis.
Supplementary Information: The online version contains supplementary material available at 10.1007/s10616-025-00759-x.

Keywords:  Atherosclerosis; CircSirt1; Circular RNA; Glutamine metabolism; VSMCs; miR-27b-3p

DOI:  https://doi.org/10.1007/s10616-025-00759-x
Mol Cell Oncol. 2025 ;12(1): 2518773

GSTP1 knockdown induces metabolic changes affecting energy production and lipid balance in pancreatic cancer cells.

Jenna N Duttenhefner, Katie M Reindl.

  Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with limited treatment options, underscoring the need for novel therapeutic targets. Metabolic reprogramming is a hallmark of PDAC, enabling tumor cells to sustain rapid proliferation and survive under nutrient-deprived conditions. While glutathione S-transferase pi 1 (GSTP1) is a known regulator of redox homeostasis in PDAC, its role in metabolic adaptation remains unclear. Here, we show that GSTP1 knockdown disrupts PDAC metabolism, leading to downregulation of key metabolic enzymes (ALDH7A1, CPT1A, SLC2A3, PGM1), ATP depletion, mitochondrial dysfunction, and phospholipid remodeling. Phospholipid remodeling, including an increase in phosphatidylcholine (PC) levels, further suggests a compensatory response to metabolic stress. Importantly, GSTP1 knockdown led to elevated lipid peroxidation, increasing 4-hydroxynonenal (4-HNE) accumulation. Treatment with the antioxidant N-acetyl cysteine (NAC) partially restored metabolic gene expression, reinforcing GSTP1's role in the interplay between redox regulation and metabolism in PDAC. By disrupting multiple metabolic pathways, GSTP1 depletion creates potential therapeutic vulnerabilities that could be targeted through metabolic and oxidative stress-inducing therapies to enhance treatment efficacy.

Keywords:  Pancreatic ductal adenocarcinoma; glutathione S-transferase pi 1 (GSTP1); metabolic reprogramming; metabolomics; therapeutic targeting

DOI:  https://doi.org/10.1080/23723556.2025.2518773
Clin Exp Immunol. 2025 Jun 14. pii: uxaf028. [Epub ahead of print]

Uncovering metabolic pathways in human alveolar macrophages in response to lipopolysaccharide.

Christine C A van Linge, Erik H A Michels, Liza Pereverzeva, Regina de Beer, Augustijn M Klarenbeek, Bauke V Schomakers, Michel van Weeghel, Riekelt H Houtkooper, W Joost Wiersinga, Peter I Bonta, Jouke T Annema, Tom van der Poll, Alex F de Vos.

   INTRODUCTION: Alveolar macrophages (AMs) play an essential role in maintaining homeostasis in the lung and in innate immunity for host defense. To fuel inflammatory responses, AMs do not rely on glycolysis, but require oxidative phosphorylation. However, which nutrients AMs use to fuel their energy demand during inflammatory responses, is still unknown. The present study aimed to determine the contribution of three key metabolic pathways; fatty acid oxidation, glutaminolysis, and glycogenolysis, to the inflammatory response of AMs.
METHODS: Primary AMs were isolated from healthy human volunteers and stimulated with lipopolysaccharide (LPS). After 24 hours, cells were subjected to analyses of metabolic flux, expression of genes involved in these metabolic pathways, and inflammatory cytokine secretion in the presence of metabolic inhibitors.
RESULTS: The results of our study show that human AMs display expression of genes involved in fatty acid and glutamine metabolism and are capable of metabolizing oleic acid and glutamine during homeostasis, but do not use these metabolites to fuel the production of inflammatory cytokines. We demonstrate that AMs, while residing in a glucose-deprived environment, contain glycogen and use glycogenolysis to fuel inflammatory cytokine secretion, as reflected by reduced TNF, IL-1βand IL-6 levels in supernatant of LPS-stimulated AMs treated with the glycogenolysis inhibitor CP316819. Moreover, AMs display marked expression of genes involved in glycogenesis, including FBP1 and GYS.
CONCLUSION: Taken together, these results indicate that primary human AMs are equipped to use different nutrients to fuel their metabolic demands. Moreover, our findings suggest that glycogenolysis is critical for the inflammatory response of AMs.

Keywords:  Cellular Immunology; Lipopolysaccharide; Macrophage; Metabolism

DOI:  https://doi.org/10.1093/cei/uxaf028
Nat Commun. 2025 Jun 20. 16(1): 5355

Iron deficiency causes aspartate-sensitive dysfunction in CD8+ T cells.

Megan R Teh, Nancy Gudgeon, Joe N Frost, Linda V Sinclair, Alastair L Smith, Christopher L Millington, Barbara Kronsteiner, Jennie Roberts, Bryan P Marzullo, Hannah Murray, Alexandra E Preston, Victoria Stavrou, Jan Rehwinkel, Thomas A Milne, Daniel A Tennant, Susanna J Dunachie, Andrew E Armitage, Sarah Dimeloe, Hal Drakesmith.

Iron is an irreplaceable co-factor for metabolism. Iron deficiency affects >1 billion people and decreased iron availability impairs immunity. Nevertheless, how iron deprivation impacts immune cell function remains poorly characterised. We interrogate how physiologically low iron availability affects CD8+ T cell metabolism and function, using multi-omic and metabolic labelling approaches. Iron limitation does not substantially alter initial post-activation increases in cell size and CD25 upregulation. However, low iron profoundly stalls proliferation (without influencing cell viability), alters histone methylation status, gene expression, and disrupts mitochondrial membrane potential. Glucose and glutamine metabolism in the TCA cycle is limited and partially reverses to a reductive trajectory. Previous studies identified mitochondria-derived aspartate as crucial for proliferation of transformed cells. Despite aberrant TCA cycling, aspartate is increased in stalled iron deficient CD8+ T cells but is not utilised for nucleotide synthesis, likely due to trapping within depolarised mitochondria. Exogenous aspartate markedly rescues expansion and some functions of severely iron-deficient CD8+ T cells. Overall, iron scarcity creates a mitochondrial-located metabolic bottleneck, which is bypassed by supplying inhibited biochemical processes with aspartate. These findings reveal molecular consequences of iron deficiency for CD8+ T cell function, providing mechanistic insight into the basis for immune impairment during iron deficiency.

DOI: https://doi.org/10.1038/s41467-025-60204-7
J Transl Med. 2025 Jun 13. 23(1): 654

Proteomic and metabolomic analysis of platelet related samples reveals energy metabolism disorders in hepatocellular carcinoma.

Xuelian Ruan, Zuojian Hu, Fenglin Shen, Yongling Chen, Ziqing Zhong, Guiyong Ou, Xing Luo, Xue Qin, Huabing Wang.

   BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most prevalent cancers in the world. Platelets play an important role in thrombosis, inflammation, and tumors. This study tries to gain a pathway-based view of platelets-related samples for understanding metabolic disorders and identifying novel biomarkers in HCC by combining proteomics and metabolomics.
METHODS: Forty-five HCC patients and thirty-four healthy controls were included in the study. We performed label-free proteomic analysis of platelets from 14 HCC patients and 14 healthy controls. Target metabolomics analysis was performed on platelet-rich plasma (PRP) from 31 HCC patients and 20 healthy controls. Western blotting was performed to validate the results of proteomics. Glutamine (Gln) deprivation assay was conducted to evaluate the effect of Gln metabolism on the platelet-induced proliferation, migration, and invasion of HCC cells.
RESULTS: Proteomics analysis revealed dysregulation of platelets function and energy metabolism in HCC patients compared with healthy controls. Target metabolomics analysis showed widespread dysregulation of amino acids in HCC patients. Integrating analysis of differential proteins and metabolites revealed five significant dysregulated pathways in HCC patients. Western blotting validation results showed that the expression levels of SDHB, CISY, and FUMH were significantly up-regulated in HCC patients compared to healthy controls, which was consistent with the proteomics findings. Biological function revealed that Gln-free weakens the ability of platelet-induced proliferation, migration, and invasion of HCC cells. Diagnostic evaluation demonstrated superior discriminatory power for SDHB (AUC = 0.929) compared to alpha-fetoprotein (AFP) in platelet proteomics. Furthermore, a triad of tricarboxylic acid cycle intermediates (succinic acid, fumaric acid, and malic acid) significantly enhanced the AUC, specificity, and sensitivity of distinguishing HCC patients from healthy controls compared to AFP.
CONCLUSIONS: Through multi-omics characterization of platelets-related samples, the network of altered proteins and metabolites provides a comprehensive view of altered metabolism in the peripheral circulation of HCC patients. Gln deprivation inhibited the ability of platelet-induced malignant biology function in HCC cells. Collectively, proteomics and metabolomics provide evidence for possible future non-invasive or minimally invasive biopsies for patients with HCC.

Keywords:  Biomarkers; Hepatocellular carcinoma; Omics; Platelet; Platelet-rich plasma

DOI:  https://doi.org/10.1186/s12967-025-06694-x
Cell Mol Biol Lett. 2025 Jun 16. 30(1): 72

The crucial role of metabolic reprogramming in driving macrophage conversion in kidney disease.

Na Gong, Wenjuan Wang, Yifei Fu, Xumin Zheng, Xinru Guo, Yuhao Chen, Yan Chen, Shengchun Zheng, Guangyan Cai.

  Interstitial fibrosis after acute kidney injury is an ongoing pathological process of chronic inflammatory injury and repair. Macrophages participate in renal inflammation, repair and fibrosis by continuously changing their phenotype and function. The tissue microenvironment of kidney injury induces changes in key metabolic enzymes, pathways and metabolites in macrophages, leading to phenotypic and functional conversions, but the detailed mechanisms are unclear. However, in the early phase of acute kidney injury, macrophages shift to a pro-inflammatory role relying on glycolysis and pentose phosphate pathways. The tissue microenvironment regulates the suppression of glycolysis-related genes and the up-regulation of oxidative phosphorylation and tricarboxylic acid cycle genes in macrophages, resulting in a gradual shift to an anti-inflammatory phenotype, which is involved in tissue repair and remodelling. In the late stage of injury, if macrophages continue to be overactive, they will be involved in renal fibrosis. The concomitant enhancement of nucleotide and amino acid metabolism, especially arginine and glutamine metabolism, is critical for the macrophage function and phenotypic transition during the above injury process. Macrophage metabolic reprogramming therefore provides new therapeutic targets for intervention in inflammatory injury and interstitial fibrosis in kidney disease.

Keywords:  Inflammation; Injury and repair; Kidney fibrosis; Macrophages; Metabolic reprogramming

DOI:  https://doi.org/10.1186/s11658-025-00746-2
Int J Med Sci. 2025 ;22(11): 2852-2876

Fructose Metabolism in Cancer: Molecular Mechanisms and Therapeutic Implications.

Xinyi Chen, Mu Yang, Lu Wang, Jingyao Tu, Xianglin Yuan.

  Metabolic reprogramming enables cancer cells to adapt to the tumor microenvironment, facilitating their survival, proliferation, and resistance to therapy. While glucose has long been considered the primary substrate for cancer cell metabolism, recent studies have highlighted the role of fructose as an alternative carbon source. Fructose metabolism, particularly through key enzymes such as ketohexokinase (KHK) and aldolase B (ALDOB), along with the fructose transporter GLUT5, supports tumor growth, metastasis, and therapeutic resistance. This review explores the mechanisms by which fructose metabolism influences cancer progression, focusing on its metabolic pathways and its impact on the tumor microenvironment. By promoting glycolysis, lipid biosynthesis, and nucleotide production, fructose metabolism enhances the metabolic adaptability of cancer cells, especially in glucose-deprived conditions. A comprehensive understanding of these processes offers potential insights into therapeutic strategies targeting fructose metabolism for cancer treatment. However, further studies are required to fully elucidate the complex role of fructose in various malignancies.

Keywords:  aldolase; fructose metabolism; glucose transporter; ketohexokinase; metabolic reprogramming; tumor metabolism

DOI:  https://doi.org/10.7150/ijms.108549
Drug Deliv Transl Res. 2025 Jun 14.

D-mannose augments targeted radioligand-immunotherapy of prostate cancer by enhancing radiosensitivity and reshaping immune microenvironment.

Lei Tao, Bin Xu, Juan Sun, Jiangtao Yang, Fenghua Meng, Zhiyuan Zhong.

  Targeted radioligand therapy (TRT) is an emerging therapeutic modality for advanced tumors like metastatic castration-resistant prostate cancer. The patients bare, however, varying degrees of resistance to TRT, which would greatly lessen the treatment efficacy and response rate. Here, we find that oral medication of D-mannose effectively enhances the radiosensitivity of PSMA-positive murine RM1-hPSMA prostate cancer cells to TRT by suppressing glucose metabolism. This metabolic disruption not only impeded the proliferation of RM1-hPSMA cells but also augmented DNA damage within tumor cells subjected to TRT, co-promoting cell apoptosis. Interestingly, TRT-D-mannose combination strongly boosted the anti-tumor immune responses by inducing immunogenic cell death, disrupting the immune evasion mechanisms employed by tumor cells, and reducing immunosuppressive cells in the tumor. D-mannose significantly improved the TRT efficacy for highly aggressive murine RM1-hPSMA and human LNCaP Clone FGC models, without causing adverse effects. Hence, D-mannose is potentially a safe radio-sensitizer and a potent immune activator for TRT.

Keywords:  Immune response; Prostate cancer; Radio-sensitizer; Targeted radioligand therapy; Tumor microenvironment

DOI:  https://doi.org/10.1007/s13346-025-01886-w
Haematologica. 2025 Jun 19.

The STAT3-VDAC1 axis modulates mitochondrial function and plays a critical role in the survival of acute myeloid leukemia cells.

Kellen B Gil, Jamie Borg, Rosana Moreira Pereira, Anagha Inguva-Sheth, Geovana Araujo, Jeremy Rahkola, William Showers, Abby Grier, Angelo D'Alessandro, Clayton Smith, Christine McMahon, Daniel A Pollyea, Austin E Gillen, Maria L Amaya.

Signal transducer and activator of transcription 3 (STAT3) is a well-described transcription factor that mediates oxidative phosphorylation and glutamine uptake in bulk acute myeloid leukemia (AML) cells and leukemic stem cells (LSCs). STAT3 has also been shown to translocate to the mitochondria in AML cells, and phosphorylation at the serine 727 (pSTAT3 S727) residue has been shown to be especially important for STAT3's mitochondrial functions. We demonstrate that inhibition of STAT3 results in impaired mitochondrial function and decreased leukemia cell viability. We discovered a novel interaction of STAT3 with voltage-dependent anion channel 1 (VDAC1) in the mitochondria which provides a mechanism through which STAT3 modulates mitochondrial function and cell survival. Through VDAC1, STAT3 regulates calcium and oxidative phosphorylation in the mitochondria. STAT3 and VDAC1 inhibition also result in significantly reduced engraftment potential of LSCs, including primary samples resistant to venetoclax. These results implicate STAT3 as a therapeutic target in AML.

DOI: https://doi.org/10.3324/haematol.2025.287352
Food Funct. 2025 Jun 17.

Untargeted metabolomics reveals the inhibition effect of a high-fat diet on colorectal cancer tumorigenesis in obesity-resistant mice via regulating bile acid, glutathione, and glycerophospholipid metabolisms.

Qi Cheng, Kun Na, Chunsheng Xu, He Peng, Xiaojian Lin, Jiajun Chen, Yan Li, Die Wu, Menghao Du, Xingya Wang.

The interplay between high fat intake and cancer is complex and multifaceted. Contradictory results exist between obesity, high-fat diet (HFD), and colorectal cancer (CRC), necessitating further research. In this study, we investigated the effect of HFD on tumorigenesis in obesity-resistant and obesity-susceptible mouse models. Our results revealed that HFD significantly inhibited CRC HCT116 and HT-29 xenograft tumor growth in obesity-resistant BALB/c nude mice in comparison with a low-fat diet (LFD). HFD feeding did not induce increases in body weight, serum pro-inflammatory cytokines, and lipid accumulation in the liver and white adipose tissue (WAT) in nude mice. However, HFD promoted tumor growth in melanoma B16-F10-bearing C57BL/6J mice, accompanied by obesity and increased pro-inflammatory cytokine levels. Untargeted metabolomics showed that HFD induced significantly changed metabolites in serum, tumor, and liver samples of the HCT116 xenograft model. In all samples, many glycerophospholipids (e.g. LysoPE (0:0/20:1) and LysoPC (16:1)) and bile acids (e.g. glycocholic acid and chenodeoxycholic acid) were significantly reduced by HFD. Enrichment and pathway analyses suggested that bile acid biosynthesis and metabolisms of lipids, amino acids, and organic acids were significantly regulated by HFD. Additionally, the glutathione metabolism was significantly downregulated, while the TCA cycle was upregulated by HFD in tumor samples. Moreover, univariate and multivariate analyses on the differential metabolites in tumors suggested that uracil, chenodeoxycholic acid, glutathione, LysoPE (0:0/20:1), and SM (d18:1/18:0) were the main metabolite biomarkers for discrimination between LFD- and HFD-fed xenograft tumors. These findings suggest that HFD elicits an anti-tumorigenic effect against CRC in obesity-resistant BALB/c nude mice via regulating bile acid, glutathione, and glycerophospholipid metabolisms.

DOI: https://doi.org/10.1039/d4fo06132b