Saikogenin A improves ethanol-induced liver injury by targeting SIRT1 to modulate lipid metabolism

Saikogenin A improves ethanol-induced liver injury by targeting SIRT1 to modulate lipid metabolism | 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 Saikogenin A improves ethanol-induced liver injury by targeting SIRT1 to modulate lipid metabolism Yufeng Wang, Ming-zhu Jiang, Ying Feng, Jing-xian Wang, Xiang Xu, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3798644/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 21 Nov, 2024 Read the published version in Communications Biology → Version 1 posted You are reading this latest preprint version Abstract Chronic alcohol consumption leads to a spectrum of liver disorders, including steatosis, inflammation, and fibrosis, collectively known as alcohol liver disease (ALD). Steatosis is a critical hallmark of ALD, making it an important target for therapeutic intervention. Saikosaponin A (SSa), a compound found in Radix Bupleuri, has previously shown promising hepatoprotective, anti-inflammatory, and antioxidant properties. However, its role in ALD remains understudied, with direct regulatory targets and mechanisms yet to be fully elucidated in vivo. Moreover, the instability of SSa in gastric juice raises questions about the efficacy of oral SSa solutions. In this study, we employed cell-based screening models and a chronic-plus-binge ethanol-fed mouse model to investigate the protective mechanisms of SSa and its metabolite Saikogenin A (SGA), against ethanol-induced hepatocyte injury. Our RNA-seq analysis in mice unveiled that SSa primarily acts through the mTOR and PPAR-α signaling pathways in the liver. Biophysical assays and loss-of-function experiments confirmed that SGA directly binds to and modulates the activity of the SIRT1 protein, mitigating ethanol-induced cell injury via the SIRT1-mTOR-PPAR-α axis. Furthermore, our liver-specific knockdown of SIRT1 in an ALD mouse model demonstrated that the action of the liver proteins affected by oral SSa solutions is mediated through SIRT1. Significantly, SGA displayed a superior safety profile for hepatocytes compared to SSa. Our findings highlight the role of SGA in binding to the SIRT1 protein and enhancing its activity, thereby regulating hepatic fatty acid oxidation and adipogenesis in ALD. This suggests that SGA holds promise as a potential therapeutic agent for ALD. Biological sciences/Drug discovery/Pharmacology Biological sciences/Drug discovery/Pharmacology/Receptor pharmacology ALD SaikogeninA Sirtuin 1 Oxidative stress Lipogenesis Pharmacokinetics Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SupplementaryInformation.docx Cite Share Download PDF Status: Published Journal Publication published 21 Nov, 2024 Read the published version in Communications Biology → Version 1 posted 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3798644","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":265838466,"identity":"e2a98efa-fb14-49e9-bdc6-36e5209596b1","order_by":0,"name":"Yufeng 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