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Hypoxia, Metabolic Reprogramming, and Drug Resistance in Liver Cancer
Open accessAbstract
Hypoxia, low oxygen (O2) level, is a hallmark of solid cancers, especially hepatocellular carcinoma (HCC), one of the most common and fatal cancers worldwide. Hypoxia contributes to drug resistance in cancer through various molecular mechanisms. In this review, we particularly focus on the roles of hypoxia-inducible factor (HIF)-mediated metabolic reprogramming in drug resistance in HCC. Combination therapies targeting hypoxia-induced metabolic enzymes to overcome drug resistance will also be summarized. Acquisition of drug resistance is the major cause of unsatisfactory clinical outcomes of existing HCC treatments. Extra efforts to identify novel mechanisms to combat refractory hypoxic HCC are warranted for the development of more effective treatment regimens for HCC patients.
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“Intratumoral hypoxia is a major driving force for cancer progression (15–19).”
From HIF inhibitor 32-134D eradicates murine hepatocellular carcinoma in combination with anti-PD1 therapy (2022) · cites this paper as [15]
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Granata, V., Fusco, R., Pupo, D., Alfieri, A., Caranci, F., Riga, M. G., Feo, M. E. D., Sgariglia, L., Carrafiello, G., Karaboue, M. A., et al. (2025) · Infectious Agents and Cancer · doi:10.1186/s13027-025-00695-7 · Cited by 3
“Hypoxia represents a crucial factor in tumor biology and plays a significant role in resistance to both conventional and targeted therapies [71, 72].”
Shi, Q.-Y., Chi, Y., Peng, Z.-Y., Li, C., Zhao, J.-W., & Zhang, J. (2025) · Frontiers in Oncology · doi:10.3389/fonc.2025.1675018 · Cited by 3
“Cancer cells often encounter hypoxic and hypo-nutrient conditions for the huge consumption of metabolites (24).”
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“Additionally, therapies targeting the vascular remodeling and ECM changes induced by HIF could help limit metastasis by preventing tumor cell invasion and dissemination [ 52 , 53 ] .”
IRX5 Promoted SREBP1‐Mediated de Novo Fatty Acid Synthesis via HMGN4 in Hepatocellular Carcinoma
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“Many patients are diagnosed with an intermediate to advanced phase and lose the opportunity for radical surgery [5,8].”
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“In hepatocellular carcinoma, hypoxia-inducible-factor-mediated metabolic reprogramming is a crucial molecular mechanism contributing to drug resistance (25).”
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“However, drug resistance remains prevalent throughout clinical treatment, serving as a core bottleneck restricting patients’ survival benefits (Bao et al., 2021).”
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Metadata
- Authors
- Bao, M. H.-R., & Wong, C. C.-L.
- Affiliations
- University of Hong Kong (HK)
- Corresponding author
- Wong, Carmen Chak-Lui
- Venue
- Cells
- Publisher
- MDPI AG
- Published
- 2021-07-06
- Volume
- 10
- Issue
- 7
- Pages
- 1715
- ISSN
- 2073-4409 (ISSN-L)
- PMC
- PMC8304710
- OpenAlex
- W3178403391
- Cited by
- 316
- References
- 121
- Citations by year
- 2026: 35 · 2025: 75 · 2024: 84 · 2023: 71 · 2022: 48 · 2021: 3
- FWCI
- 6.27
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cells (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Program for Guangdong Introducing Innovative and Entrepreneurial Teams (2019BT02Y198)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Ferroptosis and cancer prognosis
- Keywords
- hepatocellular carcinoma, tumor hypoxia, metabolic reprogramming, drug resistance, hypoxia-inducible factor, combination therapy, liver cancer treatment
- MeSH terms
- Sorafenib, Nivolumab, Pyruvate Dehydrogenase Acetyl-Transferring Kinase, Immune Checkpoint Inhibitors, Hypoxia, Antineoplastic Agents, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Gene Expression Regulation, Neoplastic, Drug Resistance, Neoplasm, Protein Kinase Inhibitors, Hypoxia-Inducible Factor 1, alpha Subunit, Metabolic Networks and Pathways, Tumor Microenvironment, Antibodies, Monoclonal, Humanized, Cellular Reprogramming
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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