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Novel Metabolism-Related Biomarkers in Cancer

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Bioorganic Chemistry".

Deadline for manuscript submissions: 31 March 2026 | Viewed by 7391

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Special Issue Editors

Dr. Maria de Fátima Monginho Baltazar

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Guest Editor

1. School of Medicine, University of Minho, 4710-057 Braga, Portugal
2. ICVS/3B's PT Government Associate Laboratory, 4710-057 Braga, Portugal
Interests: cancer glycolytic metabolism; new metabolic biomarkers in cancer; cancer drug resistance; drug discovery in cancer
Special Issues, Collections and Topics in MDPI journals

Dr. Julieta Alexandra Pereira Afonso

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Guest Editor

1. School of Medicine, University of Minho, 4710-057 Braga, Portugal
2. ICVS/3B's PT Government Associate Laboratory, 4710-057 Braga, Portugal
Interests: bladder cancer; chemoresistance; immunotherapy resistance; cancer metabolism; Warburg effect; monocarboxylate transporters; CD147; tumor microenvironment; cancer-associated fibroblasts
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cancer is a major global threat to public health, and validated, specific and sensitive cancer biomarkers are increasingly being used to accurately diagnose and manage cancer patients. However, patient treatment remains largely unsuccessful in the long term due to evolving metabolic alterations and intricate signaling within the challenging cancer microenvironment. Metabolic networks sustain fundamental cellular functions, from energy production to biosynthesis, to determine cellular fates. Distinct metabolic signatures are displayed by different cancer types, and increasing understanding of the hallmarks of metabolic reprogramming and plasticity in cancer cells is generating novel metabolism-related biomarkers that show promise in further advancing personalized medicine and improving patients’ outcomes. This Special Issue will highlight recent developments in cancer metabolism-related biomarkers’ discovery and validation, encompassing not only the historical Warburg fundamentals of the glycolytic phenotype, but also other metabolic patterns, such as amino acid, lipid and trace element metabolism, that will certainly contribute to deciphering cancer complexity and aid in directing future therapeutic interventions.

Dr. Maria de Fátima Monginho Baltazar
Dr. Julieta Alexandra Pereira Afonso
Guest Editors

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Keywords

cancer biomarkers
personalized medicine
metabolism
glucose
amino acid
glutamine
lipid
iron

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Published Papers (5 papers)

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Research

19 pages, 4981 KB

Open AccessArticle

Functional and Mechanistic Insights of 3-Hydroxybutyrate (3-OBA) in Bladder Cancer

by Ana Silva, Ana Mafalda Félix, Céline S. Gonçalves, Adhemar Longatto-Filho, Fátima Baltazar and Julieta Afonso

Molecules 2025, 30(23), 4624; https://doi.org/10.3390/molecules30234624 - 2 Dec 2025

Viewed by 203

Abstract

Bladder cancer (BC), particularly muscle-invasive urothelial bladder carcinoma (UBC), remains a clinical challenge due to frequent recurrence, chemoresistance, and limited treatment options. This study investigates the functional and mechanistic insights of 3-hydroxybutyrate (3-OBA), a ketone body with known metabolic and epigenetic roles, in muscle-invasive UBC models. 3-OBA significantly inhibited cell viability, proliferation, migration, and invasion in T24 and HT1376 cell lines in a dose-dependent manner. In vivo, 3-OBA impaired tumor growth and angiogenesis in the chick chorioallantoic membrane model. Mechanistically, 3-OBA did not alter the expression of the G-protein-coupled lactate receptor GPR81 or associated markers (phospho-ERK1/2, LDHA, MCT1/4, CD147), indicating its antitumor effects are GPR81-independent. Moreover, extracellular lactate modulation upon 3-OBA treatment varied between cell lines, with HT1376 cells showing reduced lactate production under nutrient deprivation, suggesting cell-specific metabolic responses to 3-OBA. These findings highlight 3-OBA’s potential as a metabolic modulator with antitumor efficacy in UBC, particularly in metabolically constrained tumors. However, its dual role—as both a potential energy source and therapeutic agent—demands context-specific investigation. Future studies should focus on patient stratification and preclinical validation to clarify 3-OBA’s therapeutic window and mechanism of action in bladder cancer. Full article

(This article belongs to the Special Issue Novel Metabolism-Related Biomarkers in Cancer)

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22 pages, 5059 KB

Open AccessArticle

Exometabolome and Molecular Signatures Associated with HPV 16 in Cervical Cancer: Integrative Metabolomic and Transcriptomic Analysis for Biomarker Discovery

by Adán Arizmendi-Izazaga, Napoleón Navarro-Tito, Gabriela Elizabeth Campos-Viguri, Hilda Jiménez-Wences, Macdiel Emilio Acevedo-Quiroz, Eric Genaro Salmerón-Bárcenas, Berenice Illades-Aguiar, Marco Antonio Leyva-Vázquez and Julio Ortiz-Ortiz

Molecules 2025, 30(19), 3909; https://doi.org/10.3390/molecules30193909 - 28 Sep 2025

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Abstract

Cervical cancer (CC) represents a major public health concern, ranking as the fourth most frequently diagnosed cancer and one of the leading causes of cancer-related mortality among middle-aged women worldwide. CC is caused by persistent infection with high-risk human papillomaviruses (HR-HPVs), with HPV 16 being the cause of more than 50% of CC cases. In this study, the exometabolome of the HPV 16-positive cell lines SiHa and Ca Ski, as well as the HPV 16-negative control cell line C-33 A, was evaluated. The exometabolome was validated through molecular signatures using a transcriptomic approach to identify genes encoding cellular metabolic enzymes. The exometabolome was analyzed using ¹H nuclear magnetic resonance spectroscopy (¹H-NMR). Exometabolomic profiles were subsequently compared through both multivariate and univariate statistical analyses to identify significant differences between cell lines. Molecular signatures were analyzed from the GSE9750 dataset obtained from the GEO database. Exometabolic profiling of the HPV 16 positive cell lines showed higher concentrations of leucine, isoleucine, valine, lysine, methionine, glutamine, ornithine, choline, glucose, and tryptophan. An expression analysis showed increased expression of enzymes involved in amino acid synthesis, the tricarboxylic acid cycle, glycolysis, the pentose phosphate pathway, galactose metabolism, and HIF-1α. These data suggest metabolites and metabolism-associated genes that can be used as non-invasive, stable diagnostic and prognostic biomarkers, as well as therapeutic targets for CC in the presence of HPV 16. Full article

(This article belongs to the Special Issue Novel Metabolism-Related Biomarkers in Cancer)

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27 pages, 3015 KB

Open AccessArticle

Effects of Asprosin and Role of TLR4 as a Biomarker in Endometrial Cancer

by Rebecca Karkia, Cristina Sisu, Sayeh Saravi, Ioannis Kyrou, Harpal S. Randeva, Jayanta Chatterjee and Emmanouil Karteris

Molecules 2025, 30(16), 3410; https://doi.org/10.3390/molecules30163410 - 18 Aug 2025

Cited by 1 | Viewed by 1420

Abstract

(1) Background: Following the discovery of the adipokine/hormone asprosin, a substantial amount of research has provided evidence for its role in the regulation of glucose homeostasis, as well as appetite, and insulin sensitivity. Its levels are dysregulated in certain disease states, including breast cancer. To date, little is known about its role in endometrial cancer (EC). The present study investigated the effects of asprosin on the transcriptome of the Ishikawa and NOU-1 EC cell lines, and assessed the expression of asprosin’s candidate receptors (TLR4, PTPRD, and OR4M1) in health and disease. (2) Methods: tissue culture, RNA extraction, RNA sequencing, reverse transcription-quantitative PCR, gene enrichment and in silico analyses were used for this study. (3) Results: TLR4 and PTPRD were significantly downregulated in EC when compared to healthy controls. TLR4 appeared to have a prognostic role in terms of overall survival (OS) in EC patients (i.e., higher expression, better OS). RNA sequencing revealed that asprosin affected 289 differentially expressed genes (DEGs) in Ishikawa cells and 307 DEGs in NOU-1 cells. Pathway enrichment included apoptosis, glycolysis, hypoxia, and PI3K/AKT/ mTOR/NOTCH signalling for Ishikawa-treated cells. In NOU-1, enriched processes included inflammatory response, epithelial-mesenchymal transition, reactive oxygen species pathways, and interferon gamma responses. Other signalling pathways included mTORC1, DNA repair, and p53, amongst others. (4) Conclusions: These findings underscore the importance of understanding receptor dynamics and signalling pathways in the context of asprosin’s role in EC, and provide evidence for a potential role of TLR4 as a diagnostic biomarker. Full article

(This article belongs to the Special Issue Novel Metabolism-Related Biomarkers in Cancer)

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25 pages, 3010 KB

Open AccessArticle

The Oncometabolite 2-Hydroxyglutarate Is Upregulated in Post-Prostatectomy PSA Recurrence of Prostate Cancer: A Metabolomic Analysis

by Dontrel W. Spencer Hairston, Shamira Sridharan-Weaver, Abheek Gandhi, Neelu Batra, Blythe P. Durbin-Johnson, Marc A. Dall’Era and Paramita M. Ghosh

Molecules 2025, 30(16), 3316; https://doi.org/10.3390/molecules30163316 - 8 Aug 2025

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Abstract

First-line treatment for localized prostate cancer (PCa) includes radical prostatectomy (RP) for high-risk disease. However, in many cases, patients experience biochemical recurrence (BCR), heralded by rising prostate specific antigen (PSA) levels in the serum. Our goal was to identify metabolic pathways that are disrupted in BCR to determine potential targets of therapy. We conducted metabolomic analysis in prostate tissue from the tumors of 74 patients who underwent prostatectomy as treatment for localized PCa and correlated levels of metabolites with clinical and non-clinical factors. Cholesterol and triglycerides were upregulated in Hispanic vs. non-Hispanic and in obese vs. non-obese individuals, respectively. Both lipids and non-lipids were altered with increasing Gleason grades and clinical stages. High post-RP PSA (>0.1 ng/mL) indicated recurrence (p = 0.0094) and correlated with alterations in 141 metabolites including 114 lipids and 26 non-lipid molecules. The largest increase with high post-RP PSA was in 2-hydroxyglutaric acid (2-HG), a product of the tricarboxylic acid (TCA) cycle, that had previously been established as an oncometabolite in other cancers. 2-HG was highly selective and specific for high post-RP PSA (AUC = 0.8526; p = 0.0002) while Kaplan–Meier curves indicated that among patients who recurred, high 2-HG in the tumor reduced time-to-recurrence from 84 months (for those with low 2-HG) to 38 months (for those with high 2-HG). The addition of D2HG, an enantiomer of 2-HG, increased the growth rate of LNCaP and C4 cells, and also increased Akt and ERK phosphorylation. 2-HG is upregulated in PCa tumors from patients who experience high post-RP PSA indicative of recurrence. Future studies may target this metabolite to prevent recurrent disease. Full article

(This article belongs to the Special Issue Novel Metabolism-Related Biomarkers in Cancer)

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32 pages, 6041 KB

Open AccessArticle

Glucagon and Glucose Availability Influence Metabolic Heterogeneity and Malignancy in Pancreatic Neuroendocrine Tumour (pNET) Cells: Novel Routes for Therapeutic Targeting

by Bárbara Ferreira, Isabel Lemos, Cindy Mendes, Beatriz Chumbinho, Fernanda Silva, Daniela Pereira, Emanuel Vigia, Luís G. Gonçalves, António Figueiredo, Daniela Cavaco and Jacinta Serpa

Molecules 2025, 30(13), 2736; https://doi.org/10.3390/molecules30132736 - 25 Jun 2025

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Abstract

Cancer metabolism is a hallmark of cancer. However, the impact of systemic metabolism and diet on tumour evolution is less understood. This study delves into the role of glucagon, as a component of the pancreatic microenvironment, in regulating features of pancreatic neuroendocrine tumour (pNET) cells and the metabolic remodelling occurring in the presence and absence of glucose. pNET cell lines (BON-1 and QGP-1) and the non-malignant pancreatic α-TC1 cell line were used as models. Results showed that pNET cells responded differently to glucose deprivation than α-TC1 cells. Specifically, pNET cells upregulated the GCGR in the absence of glucose, while α-TC1 cells did so in high-glucose conditions, allowing the glucagon-related pERK1/2 activation under these conditions in pNET cells. Glucagon enhanced cancerous features in pNET BON-1 cells under glucose-deprived and hyperglucagonemia-compatible concentrations. In the α-TC1 cell line, glucagon modulated cell features under high-glucose and physiological glucagon levels. NMR exometabolome analysis revealed differences in metabolic processes based on glucose availability and glucagon stimulation across cell lines, highlighting amino acid metabolism, glycolysis, and gluconeogenesis. The expression of metabolic genes was consistent with these findings. Interestingly, QGP-1 and α-TC1 cells produced glucose in no-glucose conditions, and glucagon upregulated glucose production in α-TC1 cells. This suggests that gluconeogenesis may be beneficial for some pNET subsets, pointing out novel metabolism-based strategies to manage pNETs, as well as a step forward in endocrinology and systemic metabolism. The association between GCGR expression and malignancy and a negative correlation between glucagon receptor (GCGR) and glucagon-like peptide-1 receptor (GLP-1R) expression was observed, indicating a biological role of glucagon in pNETs that deserves to be explored. Full article

(This article belongs to the Special Issue Novel Metabolism-Related Biomarkers in Cancer)

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