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Cited by 3Cancer, Hypoxia, and MetabolismMetabolism, Diabetes, and CancerCancer and biochemical research

Investigation and Distinction of Energy Metabolism in Proliferating Hepatocytes and Hepatocellular Carcinoma Cells

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Nerusch, Julia, Schicht, Gerda, Herzog, Natalie, Küpper, Jan-Heiner, Seehofer, Daniel, Damm, Georg·2025·Cells
DOI 10.3390/cells14161254PMC PMC12384642
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Abstract

Metabolic rewiring is a hallmark of both hepatic regeneration and malignant transformation, complicating the identification of cancer-specific traits. This study aimed to distinguish the metabolic profiles of proliferating hepatocytes and hepatocellular carcinoma (HCC) cells through integrated analyses of mRNA and protein expression, along with functional characterization. We compared non-malignant Upcyte® hepatocytes (HepaFH3) cultured under proliferative and confluent conditions with primary human hepatocytes, primary human hepatoma cells, and hepatoma cell lines. Proliferating HepaFH3 cells exhibited features of metabolic reprogramming, including elevated glycolysis, increased HIF1A expression, and ketone body accumulation, while maintaining low c-MYC expression and reduced BDH1 levels, distinguishing them from malignant models. In contrast, HCC cells showed upregulation of HK2, c-MYC, and BDH1, reflecting a shift toward aggressive glycolytic and ketolytic metabolism. Functional assays supported the transcript and protein expression data, demonstrating increased glucose uptake, elevated lactate secretion, and reduced glycogen storage in both proliferating and malignant cells. These findings reveal that cancer-like metabolic changes also occur during hepatic regeneration, limiting the diagnostic utility of individual metabolic markers. HepaFH3 cells thus provide a physiologically relevant in vitro model to study regeneration-associated metabolic adaptation and may offer insights that contribute to distinguishing regenerative from malignant processes. Our findings highlight the potential of integrated metabolic profiling in differentiating proliferation from tumorigenesis.

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  • HepG2 expresses high-affinity hexokinase II (HK2) instead of glucokinase (GCK), maintaining high glycolysis even at low glucose.

    “While mature hepatocytes express glucokinase (GCK, hexokinase IV), whose activity is regulated by physiological glucose concentrations and insulin, GCK expression is suppressed in HepG2 cells, which produce high-affinity hexokinase II (HK2) [116,117,118].”

    From The HepG2 Cell Line as a Model for Studying Metabolic Dysfunction-Associated Steatotic Liver Disease (2026) · cites this paper as [118]

    The Introduction describes HK2 as having higher glucose affinity than GCK, and the Results (section 3.2) report elevated HK2 and reduced GCK expression in HepG2 and Huh7 cells. The paper also reports enhanced glycolytic activity, but the supplied passages do not establish that HepG2 maintains high glycolysis specifically at low glucose; that detail appears in the paraphrased claim, not the verbatim citing sentence. (LLM, conf=0.84)

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Cited by

Sorted by citations

Authors
Nerusch, J., Schicht, G., Herzog, N., Küpper, J.-H., Seehofer, D., & Damm, G.
Affiliations
  • University Hospital Leipzig (DE)
  • Brandenburg University of Technology Cottbus-Senftenberg (DE)
Corresponding author
Damm, Georg
ORCID
Venue
Cells
Publisher
MDPI AG
Published
2025-08-14
Volume
14
Issue
16
Pages
1254
ISSN
2073-4409 (ISSN-L)
DOI
10.3390/cells14161254
PMC
PMC12384642
OpenAlex
W4413970144
Cited by
3
References
6
Citations by year
2026: 2 · 2025: 1
FWCI
1.35
Type
journal article
Language
en
Open access
Licence
Locations
  • Cells (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • German Ministry of Education, Research and Space (BmFTR) (031L0256C, 031L0313C, 031L0258E, 031L0315D, 990101-113)
  • DEEP-HCC (031L0256C, 031L0313C, 031L0258E, 031L0315D, 990101-113)
  • Medical Faculty of Leipzig University (031L0256C, 031L0313C, 031L0258E, 031L0315D, 990101-113)
  • Open Access Publication Fund of Leipzig University (031L0256C, 031L0313C, 031L0258E, 031L0315D, 990101-113)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer and biochemical research
Keywords
hepatocellular carcinoma, hepatocyte proliferation, liver regeneration, metabolic reprogramming, glycolysis, ketogenesis, HIF1A, c-Myc, BDH1, HK2, lactate secretion, glycogen storage, cancer metabolism, metabolic biomarkers
MeSH terms
Energy Metabolism, Glycolysis, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Hepatocytes, Cell Line, Tumor, Cell Proliferation

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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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