Open research questions in Cancer, Hypoxia, and Metabolism
794 gap statements mined from Cancer, Hypoxia, and Metabolism papers in our 7.9M-paper local library, which holds 3,066 papers on the topic — drawn mostly from each paper's own stated research gap, future-work, challenge and limitation notes, and its abstract. The ones listed below are a selection still marked open; each names the study that raised it, with a DOI link where the paper has one.
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What the literature leaves open
The lack of consideration of erythrocyte intracellular glucose exposure in the interpretation of HbA1c values. The need for a framework that complements established explanations for HbA1c discordance.
HbA1c reconsidered: glycated haemoglobin in the era of dynamic erythrocyte glucose metabolism · 2026 · DOIThe molecular mechanisms of cancer cell metabolism are not fully understood. The study aims to investigate the metabolic links between mitochondrial electron transport, glycolysis, and AMP-activated protein kinase signaling.
Metabolic links between mitochondrial electron transport, glycolysis, and AMP-activated protein kinase signaling modulate hepatocellular carcinoma cell survival · 2026 · DOIIt highlights the need for therapeutic strategies that target metabolic rewiring in glioblastoma. The paper notes that current therapies often fail to account for the complex metabolic landscape of glioblastoma.
The Impact of Metabolic Rewiring in Glioblastoma: The Immune Landscape and Therapeutic Strategies · 2025 · DOIThe mechanisms of hypoxia-driven tumor adaptation are not fully understood. The impact of hypoxia on cellular junctions and the tumor microenvironment is not well characterized.
HIF-1α-Mediated Disruption of Cellular Junctions: The Impact of Hypoxia on the Tumor Microenvironment and Invasion · 2025 · DOITherapies targeting glycolysis enzymes responsible for the Warburg effect have not yet reached widespread clinical practice. The extensive use of glycolysis by multiple tissues in the human body introduces the challenge of potential side effects.
The need for a comprehensive understanding of the role of HIF-1α in solid tumors. The lack of knowledge on the molecular mechanisms of HIF-1α regulation and its effects on tumor progression.
A Molecular Perspective on HIF-1α and Angiogenic Stimulator Networks and Their Role in Solid Tumors: An Update · 2024 · DOIThe authors faced challenges in producing a ZIF-90 product free from contaminants due to the lack of necessary chemical synthesis equipment. The study required the use of specific instruments, including a laboratory oven and a Thermo Scientific NanoDrop 2000 photospectrometer.
ZIF-8 as a pH-Responsive Nanoplatform for 5-Fluorouracil Delivery in the Chemotherapy of Oral Squamous Cell Carcinoma · 2024 · DOIIt highlights the need to explore the mechanisms of action of natural products in influencing cellular energetics. The study aims to provide a solid ground for researchers to consider natural products in cancer treatment.
Natural Products and Altered Metabolism in Cancer: Therapeutic Targets and Mechanisms of Action · 2024 · DOIA comprehensive understanding of the roles of HIFs in the retina is lacking. The mechanisms by which HIFs regulate oxygen homeostasis and cellular metabolism in the retina are not fully understood. The potential therapeutic targets for managing disease development and progression are not well established.
The transcriptional regulators that set metabolic state, however, remain poorly defined.
Hyperactivation of β-catenin rewires mitochondrial fuel selection in liver cancer cells · 2026 · DOIHowever, their contribution to metabolic adaptation in pancreatic cancer remains poorly understood.
Testis-Specific MAGEA3/6 Regulate Glycolysis to Promote Metabolic Flexibility and Reveal Therapeutic Vulnerabilities in Pancreatic Cancer Cells · 2026 · DOIThe molecular mechanisms through which acidosis affects essential cellular processes are unclear. The relationship between extracellular acidosis and ribosome biogenesis is not well understood. The role of oxidative stress in nucleolar stress induction is not fully elucidated.
Platelet-type phosphofructokinase (PFKP), a key rate-limiting enzyme in glycolysis, is involved in tumor metabolic reprogramming, but its role in HCC prognosis, immune regulation, and therapeutic responsiveness remains incompletely understood.
Platelet-Type Phosphofructokinase Drives Immune Checkpoint Coexpression and Metabolic Pathway Activation in Liver Cancer: The Cancer Genome Atlas–Based and Experimental Validation · 2026 · DOIFive weeks of aerobic training in this small sample was associated with selective changes in some mitochondrial biogenesis markers, but there was insufficient evidence for a significant effect on the progression of tumor growth or PGC-1α protein levels.
The effect of five weeks of aerobic training on mitochondrial biogenesis markers in breast tumor tissue of female BALB/C Mice · 2026 · DOIIn early-diverging metazoans, however, p53 metabolic functions remain poorly understood.
However, the precise role of dauriporphine in the treatment of lung cancer and its underlying biological mechanism remains unclear.
Dauriporphine Inhibits the Proliferation, Migration, Angiogenesis, and Glycolysis in Lung Cancer Cells by Repressing PGK1 Expression via CEBPA · 2026 · DOIIntratumoral hypoxia, a known adverse prognostic marker in nonpregnant BC, has not yet been studied in PrBC/PPBC.
Prognostic value of immunohistochemical markers of intratumoral hypoxia in pregnancy-associated breast cancer · 2025 · DOIThe study only investigated the anti-hypoxic activity of BFMPs-DES and BFMPs-EtOH in vitro, - The study used a limited number of cell lines and animal models, - The study did not investigate the long-term effects of BFMPs-DES and BFMPs-EtOH, - The study did not compare the effects of BFMPs-DES and BFMPs-EtOH with other…
Anti-hypoxic activity of Biyang floral mushroom polyphenols: deep eutectic solvent-based ultrasound-assisted extraction versus ethanol extraction · 2026 · DOIInvestigate the anti-hypoxic activity of BFMPs-DES and BFMPs-EtOH in vivo, - Compare the effects of BFMPs-DES and BFMPs-EtOH with other treatments, - Investigate the long-term effects of BFMPs-DES and BFMPs-EtOH, - Explore the potential of BFMPs-DES and BFMPs-EtOH in preventing or treating hypoxia-related…
Anti-hypoxic activity of Biyang floral mushroom polyphenols: deep eutectic solvent-based ultrasound-assisted extraction versus ethanol extraction · 2026 · DOIFurther study on the relationship between glycolysis and AMPK activation, - Investigation on the efficacy of siRNAs targeting respiratory complex I and III for anticancer therapeutics, - Exploration of oligonucleotide therapeutics as a next-generation modality…
Metabolic links between mitochondrial electron transport, glycolysis, and AMP-activated protein kinase signaling modulate hepatocellular carcinoma cell survival · 2026 · DOIInvestigate the effects of acidic pH on other types of cells, - Examine the long-term effects of acidic pH on cell growth and survival, - Explore the therapeutic potential of targeting the acidosis-driven stress response in solid…
Investigating how metabolic pathways in GBM adapt to heterogeneous TME-across distinct tumor zones, nutrient availability, ECM, and responses to therapies - Understanding the role of hypoxia-induced metabolic reprogramming on immune dysfunction, therapeutic resistance, and tumor cell survival - Elucidating the precise role of glutamine-derived α-ketoglutarate in tumor progression, the mechanism by which tryptophan…
The Impact of Metabolic Rewiring in Glioblastoma: The Immune Landscape and Therapeutic Strategies · 2025 · DOIInvestigating the utility of the Warburg effect as an early diagnostic tool, - Examining the multifaceted roles of lactate within the tumor microenvironment, - Developing therapeutic strategies that target glycolytic enzymes, - Investigating the potential of GLUT inhibitors as therapeutic…
The study did not explore the use of ZIF-90 due to lack of necessary chemical synthesis equipment, - The study used a limited number of cell lines, - The study did not investigate the long-term effects…
ZIF-8 as a pH-Responsive Nanoplatform for 5-Fluorouracil Delivery in the Chemotherapy of Oral Squamous Cell Carcinoma · 2024 · DOIFurther studies on the role of HIFs in retinal diseases, - Investigation of the therapeutic impacts of HIF-1 knockout in the RPE on laser-induced CNV, - Research on the molecular mechanisms of subretinal fibrosis…
Most-cited papers in Cancer, Hypoxia, and Metabolism
- Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation · Science · 2009 · 14,120 citations
- Targeting of HIF-α to the von Hippel-Lindau Ubiquitylation Complex by O 2 -Regulated Prolyl Hydroxylation · Science · 2001 · 4,832 citations
- HIFα Targeted for VHL-Mediated Destruction by Proline Hydroxylation: Implications for O 2 Sensing · Science · 2001 · 4,156 citations
- Cancer-associated IDH1 mutations produce 2-hydroxyglutarate · Nature · 2009 · 3,505 citations
- A pathology atlas of the human cancer transcriptome · Science · 2017 · 2,988 citations
- The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth · Nature · 2008 · 2,391 citations
- Metabolic reprogramming and cancer progression · Science · 2020 · 2,363 citations
- Hypoxia and Inflammation · New England Journal of Medicine · 2011 · 1,862 citations
- The role of ROS in tumour development and progression · Nature reviews. Cancer · 2022 · 1,518 citations
- The hallmarks of cancer metabolism: Still emerging · Cell Metabolism · 2022 · 1,319 citations
Most recent work
- Lactate: elucidating its indispensable role in human health · Molecular Cancer · 2026
- Metabolic reprogramming in cancer: signaling pathways and therapeutic targets · Molecular Cancer · 2026
- Targeting Lactate and Lactylation in Cancer Metabolism and Immunotherapy · Advanced Science · 2026
- Metabolic crosstalk among cancer-associated fibroblasts, adipocytes and immune cells as an immunosuppressive tumor microenvironment driver · Experimental & Molecular Medicine · 2026
- GCN5–ERK lactylation–phosphorylation loop amplifies lactate-driven cancer progression · Nature Chemical Biology · 2026
- Targeting Glycolytic Metabolism in Cancer Therapy: Current Approaches and Future Perspectives · Cells · 2026
- A Review of HIF-1α-Mediated Integration of Metabolic Reprogramming, Mitochondrial Function, and PI3K/Akt–MAPK–Nrf2–NF-κB Signaling · Antioxidants · 2026
- Lactate-lactylation in tumor angiogenesis and progression: mechanisms, biomarker potential, and therapeutic implications · Biomarker Research · 2026
- β-hydroxybutyrate enhances the metabolic fitness of CAR T cells in cancer · Cell · 2026
- Lactylation in cancer: mechanistic insights, tumor microenvironment, and therapeutic horizons · Frontiers in Immunology · 2026
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