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L-ascorbate prevents non-alcoholic steatohepatitis-based hepatocarcinogenesis in Sod1/Prdx4 double-knockout mice

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Osaki, Tsukasa, Homma, Takujiro, Maeda, Yuki, Yamada, Ken-ichi, Yokoyama, Chikako, Toyokuni, Shinya, Fujii, Junichi·2025·Scientific Reports
DOI 10.1038/s41598-025-28982-8PMC PMC12722311

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Abstract

Superoxide dismutase 1 (Sod1) and peroxiredoxin 4 (Prdx4) double knockout (DKO) causes symptoms similar to non-alcoholic steatohepatitis (NASH) even at younger ages. This study revealed that DKO mice exhibited high mortality, and surviving DKO mice developed hepatocellular carcinoma within the first year of life. Administration of physiological doses of L-ascorbate (Asc; 1.5 mg/mL) in drinking water reduced mortality and effectively prevented tumor development. Oxidative stress due to SOD1 deficiency and endoplasmic reticulum stress due to PRDX4 deficiency may promote NASH, ultimately leading to hepatocarcinogenesis. Analyses of liver tissues from 8-month-old DKO mice revealed that Asc supplementation robustly suppressed upregulation of amino acid metabolic pathways observed in DKO mice. These findings suggest that upregulation of amino acid metabolic pathways may be important for the hepatocarcinogenesis. An iron-regulatory protein and aconitase activity were decreased in DKO mice regardless of Asc status. Furthermore, precancerous lesions were more reactive to a ferroptosis-specific antibody than tumor lesions. These results suggest that Asc supplementation and aberrant iron metabolism selectively induce the death of cells that lead to tumorigenic proliferation at the precancerous stage. Adequate intake of Asc in daily life may improve the tumorigenic process promoted by hepatic steatosis due to oxidative insult.

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Fig. 1 Asc alleviated tumor development and mortality in DKO mice. (A) Plasma Asc levels were measured using a fluorescent probe. The number of animals is indicated in parentheses. Statistical analysis was performed using one-way ANOVA followed by the Tukey‒Kramer test. **P < 0.01; ***P < 0.001. (B) Male DKO mice with (1.5 mg/mL in drinking water) or without Asc supplementation were observed for up to one year (n = 20 per group). Survival curves were compared using the log-rank test (P = 0.0425). (C) Representative livers from DKO mice at 12 months (12 Mo). After one year, mice were euthanized and the numbers of visible hepatic tumors were determined. The incidence of tumor-bearing mice was compared among the four genetic groups. Chi-square analysis revealed P-values of 0.6714, 0.0935, and 0.0007 for Prdx4-KO, Sod1-KO, and DKO groups, respectively, compared with WT. Asc was supplemented in Sod1-KO and DKO groups. Chi-square analysis showed a significant difference in tumor incidence between groups with and without Asc (P = 0.0510 for Sod1KO mice and P = 0.0019 for DKO mice).
Fig. 1 Asc alleviated tumor development and mortality in DKO mice. (A) Plasma Asc levels were measured using a fluorescent probe. The number of animals is indicated in parentheses. Statistical analysis was performed using one-way ANOVA followed by the Tukey‒Kramer test. **P < 0.01; ***P < 0.001. (B) Male DKO mice with (1.5 mg/mL in drinking water) or without Asc supplementation were observed for up to one year (n = 20 per group). Survival curves were compared using the log-rank test (P = 0.0425). (C) Representative livers from DKO mice at 12 months (12 Mo). After one year, mice were euthanized and the numbers of visible hepatic tumors were determined. The incidence of tumor-bearing mice was compared among the four genetic groups. Chi-square analysis revealed P-values of 0.6714, 0.0935, and 0.0007 for Prdx4-KO, Sod1-KO, and DKO groups, respectively, compared with WT. Asc was supplemented in Sod1-KO and DKO groups. Chi-square analysis showed a significant difference in tumor incidence between groups with and without Asc (P = 0.0510 for Sod1KO mice and P = 0.0019 for DKO mice).CC BY-NC-ND · PubMed Central
Fig. 2 Histological analyses of mice livers. (A) Liver Sects. (5 µm in thickness) of WT, DKO, and DKO mice supplemented with Asc (DKO + Asc) at 8 months of age were subjected to hematoxylin–eosin staining and immunohistochemical staining using FerAb. Number of animals is 4 each. (B) Cancerous and precancerous areas in the liver of a 12-month-old mouse are indicated by the dotted lines and red arrows, respectively. The right panel is an enlargement of the left panel.
Fig. 2 Histological analyses of mice livers. (A) Liver Sects. (5 µm in thickness) of WT, DKO, and DKO mice supplemented with Asc (DKO + Asc) at 8 months of age were subjected to hematoxylin–eosin staining and immunohistochemical staining using FerAb. Number of animals is 4 each. (B) Cancerous and precancerous areas in the liver of a 12-month-old mouse are indicated by the dotted lines and red arrows, respectively. The right panel is an enlargement of the left panel.CC BY-NC-ND · PubMed Central
Fig. 3 Proteomic analyses of the livers from DKO mice compared with WT mice or DKO mice with Asc supplementation. Proteins were extracted from the liver tissues of mice at 8 months of age and subjected to trypsinization followed by proteomic analyses via nanoflow liquid chromatography tandem mass spectrometry. Statistical analyses were performed using a Student’s t-test for comparisons of two groups. (A) The volcano plot of the data compares the proteins in DKO mice vs. those in WT mice (left panel) and proteins in DKO mice supplemented with Asc (DKO + Asc) vs. proteins in DKO mice (right panel). The blue and red lines indicate levels in DKO mice that were 0.67- and 1.5-fold higher than in WT mice, and 0.67- and 1.5-fold higher than in DKO mice supplemented with Asc, respectively. (B) The Venn diagram indicates the numbers of proteins that were either upregulated (left: ratio > 1.5; P-value < 0.05) or downregulated (right: ratio < 0.67; P-value < 0.05) between two mice groups. Number of animals is 3 each.
Fig. 3 Proteomic analyses of the livers from DKO mice compared with WT mice or DKO mice with Asc supplementation. Proteins were extracted from the liver tissues of mice at 8 months of age and subjected to trypsinization followed by proteomic analyses via nanoflow liquid chromatography tandem mass spectrometry. Statistical analyses were performed using a Student’s t-test for comparisons of two groups. (A) The volcano plot of the data compares the proteins in DKO mice vs. those in WT mice (left panel) and proteins in DKO mice supplemented with Asc (DKO + Asc) vs. proteins in DKO mice (right panel). The blue and red lines indicate levels in DKO mice that were 0.67- and 1.5-fold higher than in WT mice, and 0.67- and 1.5-fold higher than in DKO mice supplemented with Asc, respectively. (B) The Venn diagram indicates the numbers of proteins that were either upregulated (left: ratio > 1.5; P-value < 0.05) or downregulated (right: ratio < 0.67; P-value < 0.05) between two mice groups. Number of animals is 3 each.CC BY-NC-ND · PubMed Central
Fig. 4 Comparison of metabolites among three groups of mice at 8 months of age. Liver soluble metabolites were analyzed by liquid chromatography-tandem mass spectrometry. Statistical analyses were performed using Student’s t-test. (A) Volcano plots comparing DKO vs. WT mice (left) and DKO + Asc vs. WT mice (right). Blue and red lines indicate 0.67- and 1.5-fold thresholds, respectively. (B) Venn diagrams showing upregulated (fold change > 1.5, P < 0.05) and downregulated (fold change < 0.67, P < 0.05) metabolites between groups. Metabolites altered in DKO mice but normalized by Asc supplementation are listed. n = 3 per group. (C, D) Heatmap and PCA score plots of metabolites involved in glycometabolism (C) and amino acid metabolism (D). (E) Representative metabolites of central metabolism mapped onto glycolysis (linked to the pentose phosphate pathway), the TCA cycle, and the urea cycle.
Fig. 4 Comparison of metabolites among three groups of mice at 8 months of age. Liver soluble metabolites were analyzed by liquid chromatography-tandem mass spectrometry. Statistical analyses were performed using Student’s t-test. (A) Volcano plots comparing DKO vs. WT mice (left) and DKO + Asc vs. WT mice (right). Blue and red lines indicate 0.67- and 1.5-fold thresholds, respectively. (B) Venn diagrams showing upregulated (fold change > 1.5, P < 0.05) and downregulated (fold change < 0.67, P < 0.05) metabolites between groups. Metabolites altered in DKO mice but normalized by Asc supplementation are listed. n = 3 per group. (C, D) Heatmap and PCA score plots of metabolites involved in glycometabolism (C) and amino acid metabolism (D). (E) Representative metabolites of central metabolism mapped onto glycolysis (linked to the pentose phosphate pathway), the TCA cycle, and the urea cycle.CC BY-NC-ND · PubMed Central
Fig. 5 Upregulation of antioxidant proteins and alterations in NRF2 in the liver of 8-month-old mice. (A) Heat map of antioxidant proteins (GO: 0,006,979, response to oxidative stress; 35/412 proteins) among three groups of mice. Statistical analyses were performed by Student’s t-test. WT vs DKO mice: *P < 0.05, **P < 0.01, ***P < 0.001. WT vs DKO + Asc: #P < 0.05, ##P < 0.01, ###P < 0.001. (B) Immunoblot analysis of liver nuclear proteins with anti-NRF2 antibody (top). Signal intensity was quantified relative to histone H2A (middle). Nrf2 mRNA expression was measured by quantitative PCR relative to β-actin mRNA (bottom). Numbers in parentheses indicate the number of animals. Statistical analysis was performed using one-way ANOVA followed by the Tukey‒Kramer test. (C) Correlation between NRF2 abundance (relative to histone H2A) and body weight in each group.
Fig. 5 Upregulation of antioxidant proteins and alterations in NRF2 in the liver of 8-month-old mice. (A) Heat map of antioxidant proteins (GO: 0,006,979, response to oxidative stress; 35/412 proteins) among three groups of mice. Statistical analyses were performed by Student’s t-test. WT vs DKO mice: *P < 0.05, **P < 0.01, ***P < 0.001. WT vs DKO + Asc: #P < 0.05, ##P < 0.01, ###P < 0.001. (B) Immunoblot analysis of liver nuclear proteins with anti-NRF2 antibody (top). Signal intensity was quantified relative to histone H2A (middle). Nrf2 mRNA expression was measured by quantitative PCR relative to β-actin mRNA (bottom). Numbers in parentheses indicate the number of animals. Statistical analysis was performed using one-way ANOVA followed by the Tukey‒Kramer test. (C) Correlation between NRF2 abundance (relative to histone H2A) and body weight in each group.CC BY-NC-ND · PubMed Central
Fig. 6 Changes in the status of ACOs and iron. (A) Immunoblot analysis was performed on liver proteins using an antibody against SOD1, PRDX4, ACO1, and ACO2 and β-ACTIN. The signal intensity was quantified using ImageJ software and is expressed relative to the β-ACTIN band. ***P < 0.001. (B) Aconitase activity was determined using a commercial assay kit without a further addition of iron. **P < 0.01. (C) Iron contents were determined using an iron assay kit; n = 4 each in all experiments. Statistical analysis was performed using one-way ANOVA followed by the Tukey‒Kramer test.
Fig. 6 Changes in the status of ACOs and iron. (A) Immunoblot analysis was performed on liver proteins using an antibody against SOD1, PRDX4, ACO1, and ACO2 and β-ACTIN. The signal intensity was quantified using ImageJ software and is expressed relative to the β-ACTIN band. ***P < 0.001. (B) Aconitase activity was determined using a commercial assay kit without a further addition of iron. **P < 0.01. (C) Iron contents were determined using an iron assay kit; n = 4 each in all experiments. Statistical analysis was performed using one-way ANOVA followed by the Tukey‒Kramer test.CC BY-NC-ND · PubMed Central

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Metadata

Authors
Osaki, T., Homma, T., Maeda, Y., Yamada, K.-I., Yokoyama, C., Toyokuni, S., & Fujii, J.
Affiliations
  • Yamagata University (JP)
  • Nagoya University (JP)
  • Kyushu University (JP)
  • Osaka Metropolitan University (JP)
  • Center for Low-temperature Plasma Sciences, Nagoya University (JP)
Corresponding author
Osaki, Tsukasa
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2025-12-22
Volume
15
Issue
1
Pages
44312-44312
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/s41598-025-28982-8
PMC
PMC12722311
OpenAlex
W7116748878
Cited by
0
References
6
FWCI
0.00
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by-nc-nd)
  • Research Square (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Japan Society for the Promotion of Science (KAKENHI (23K06410), KAKENHI (JP19H05462), KAKENHI (24K10074))
  • Japan Science and Technology Agency (CREST (JPMJCR19H4))
  • Yamagata University (YU-COE program (S6))
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer and biochemical research
  • Health Sciences › Medicine › Biochemistry (medical) › Antioxidant Activity and Oxidative Stress
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
Keywords
L-ascorbate, nonalcoholic steatohepatitis, hepatocarcinogenesis, hepatocellular carcinoma, superoxide dismutase 1, peroxiredoxin 4, oxidative stress, endoplasmic reticulum stress, amino acid metabolism, iron metabolism, aconitase, iron regulatory proteins, ferroptosis, precancerous lesions, hepatic steatosis, vitamin C supplementation
MeSH terms
Superoxide Dismutase-1, Animals, Ascorbic Acid, Carcinoma, Hepatocellular, Liver, Liver Neoplasms, Male, Mice, Knockout, Oxidative Stress, Mice, Peroxiredoxins, Endoplasmic Reticulum Stress, Carcinogenesis, Non-alcoholic Fatty Liver Disease

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