Activating AMPK-p53 Axis Induced by Mitochondrial Impairment: A Novel Anti-Liver Cancer Mechanism of Sulfane Sulfur

Activating AMPK-p53 Axis Induced by Mitochondrial Impairment: A Novel Anti-Liver Cancer Mechanism of Sulfane Sulfur | 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 Research Article Activating AMPK-p53 Axis Induced by Mitochondrial Impairment: A Novel Anti-Liver Cancer Mechanism of Sulfane Sulfur Xue Zheng, Yuhua Luo, Rui Huo, Yiwen Wang, Youbang Chen, Mianrong Chen, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4668889/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer and remains refractory to conventional chemotherapy. Sulfane sulfur-based compounds have a long history in the treatment of HCC, but their efficacy has been disappointing. We recently reported a sulfane sulfur donor PSCP, which exhibits improved chemical stability and allows for greater structural modification. This study aimed to investigate the effects of PSCP on HCC and elucidate the underlying mechanisms. Bioinformatics algorithms, including clustering, function enrichment, feature screening, and survival analysis were employed to analyze the Cancer Proteome Atlas (CPTAC) proteomic data and The Cancer Genome Atlas (TCGA) transcriptomic sequencing data of HCC gene expression. The impact of PSCP on HCC were assessed both in vitro and in vivo. We evaluated the expression and activity of p53 and AMP-activated protein kinase (AMPK), as well as mitochondrial function. The molecular target of PSCP was identified using Autodock, and the binding interaction was visually analyzed. In HCC, sulfur metabolism was found to be reprogrammed and the downregulation of sulfur-related pathways was associated with poor patient prognosis. PSCP treatment inhibited HCC tumor growth in an allograft model, reduced cell viability and proliferation, but induced apoptosis. Moreover, PSCP promoted p53 expression and AMPK phosphorylation by inhibiting mitochondrial respiratory complex I. Collectively, our findings suggest that reprogramming of sulfur-related metabolic pathways is a key factor in HCC, and PSCP emerges as an effective therapeutic strategy, by activating the mitochondrial-AMPK-p53 signaling axis. KEYWORDS: Metabolic reprogramming; Hepatocellular carcinoma; Sulfane sulfur; Mitochondrial complex; AMPK; p53 Metabolic reprogramming Hepatocellular carcinoma Sulfane sulfur Mitochondrial complex AMPK p53 Full Text Supplementary Files Highlights.docx Cite Share Download PDF Status: Posted 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-4668889","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":324812365,"identity":"47ad2234-b01c-4800-bfee-47643093382b","order_by":0,"name":"Xue Zheng","email":"","orcid":"","institution":"Foshan Lecong hospital","correspondingAuthor":false,"prefix":"","firstName":"Xue","middleName":"","lastName":"Zheng","suffix":""},{"id":324812366,"identity":"bdbf13bd-4ffe-4cf8-9930-a39199faf7c1","order_by":1,"name":"Yuhua Luo","email":"","orcid":"","institution":"Guangzhou Medical College: Guangzhou Medical 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Sulfur","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Metabolic reprogramming, Hepatocellular carcinoma, Sulfane sulfur, Mitochondrial complex, AMPK, p53","lastPublishedDoi":"10.21203/rs.3.rs-4668889/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4668889/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eHepatocellular carcinoma (HCC) is the most common form of primary liver cancer and remains refractory to conventional chemotherapy. Sulfane sulfur-based compounds have a long history in the treatment of HCC, but their efficacy has been disappointing. We recently reported a sulfane sulfur donor PSCP, which exhibits improved chemical stability and allows for greater structural modification. This study aimed to investigate the effects of PSCP on HCC\u0026nbsp;and elucidate the underlying mechanisms. Bioinformatics algorithms, including clustering, function enrichment, feature screening, and survival analysis were employed to analyze the Cancer Proteome Atlas (CPTAC) proteomic data and The Cancer Genome Atlas (TCGA) transcriptomic sequencing data of HCC gene expression. The impact of PSCP on HCC were assessed both\u0026nbsp;in vitro\u0026nbsp;and\u0026nbsp;in vivo. We evaluated the expression and activity of p53 and AMP-activated protein kinase (AMPK), as well as mitochondrial function. The molecular target of PSCP was identified using Autodock, and the binding interaction was visually analyzed. In HCC, sulfur metabolism was found to be reprogrammed and the downregulation of sulfur-related pathways was associated with poor patient prognosis. PSCP treatment inhibited HCC tumor growth in an allograft model, reduced cell viability and proliferation, but induced apoptosis. Moreover, PSCP promoted p53 expression and AMPK phosphorylation by inhibiting mitochondrial respiratory complex I. Collectively, our findings suggest that reprogramming of sulfur-related metabolic pathways is a key factor in HCC, and PSCP emerges as an effective therapeutic strategy, by activating the mitochondrial-AMPK-p53 signaling axis. 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