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

L-ascorbate prevents non-alcoholic steatohepatitis-based hepatocarcinogenesis in Sod1/Prdx4 double-knockout mice | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article L-ascorbate prevents non-alcoholic steatohepatitis-based hepatocarcinogenesis in Sod1/Prdx4 double-knockout mice Tsukasa Osaki, Takujiro Homma, Yuki Maeda, Ken-ichi Yamada, Chikako Yokoyama, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7368511/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 22 Dec, 2025 Read the published version in Scientific Reports → Version 1 posted 12 You are reading this latest preprint version 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 (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 ascorbate 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 ascorbate status. Furthermore, precancerous lesions were more reactive to a ferroptosis-specific antibody than tumor lesions. These results suggest that ascorbate supplementation and aberrant iron metabolism selectively induce the death of cells that lead to tumorigenic proliferation at the precancerous stage. Adequate intake of ascorbate in daily life may improve the tumorigenic process promoted by hepatic steatosis due to oxidative insult. Biological sciences/Cancer Biological sciences/Cell biology Health sciences/Diseases Health sciences/Gastroenterology Non-alcoholic steatohepatitis Hepatic tumor Endoplasmic reticulum stress Oxidative stress Iron regulatory protein Full Text Additional Declarations No competing interests reported. Supplementary Files SupplementaryTables13.xlsx SupplementaryMethods.doc SupplentaryFigures.ppt Cite Share Download PDF Status: Published Journal Publication published 22 Dec, 2025 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 23 Sep, 2025 Reviews received at journal 12 Sep, 2025 Reviews received at journal 12 Sep, 2025 Reviews received at journal 09 Sep, 2025 Reviewers agreed at journal 30 Aug, 2025 Reviewers agreed at journal 29 Aug, 2025 Reviewers agreed at journal 29 Aug, 2025 Reviewers invited by journal 29 Aug, 2025 Editor assigned by journal 29 Aug, 2025 Editor invited by journal 27 Aug, 2025 Submission checks completed at journal 22 Aug, 2025 First submitted to journal 22 Aug, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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