Investigation of the transcription factor TEAD-based material basis of Astragalus synergistic dacarbazine in the treatment of uveal melanoma

Investigation of the transcription factor TEAD-based material basis of Astragalus synergistic dacarbazine in the treatment of uveal melanoma | 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 Investigation of the transcription factor TEAD-based material basis of Astragalus synergistic dacarbazine in the treatment of uveal melanoma Yuemei Zhang, xiqianru zhang, ruifeng wang, haotian li, hao liu, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8314542/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 8 You are reading this latest preprint version Abstract Uveal melanoma (UM) is the most common intraocular malignancy in adults, and despite great advances in combination drug therapies based on UM-related pathways, targeted therapies remain an unmet medical need, and there has been a decrease in sensitivity to chemotherapy. Astragalus, as a medicinal and edible herbs, may play a role in the treatment of cancer by combining different chemotherapeutic agents. In this study, we first found that Astragalus can be combined with dacarbazine for the treatment of uveal melanoma using a hormonal mouse model and determined that the transcription factor TEAD may be one of the reasons for the reduced sensitivity of uveal melanoma to dacarbazine chemotherapy. Subsequently, using a multidisciplinary approach of computer-aided drug design combined with cellular experiments and molecular pairing, we found that RISO, a compound in Astragalus, stabilised the binding of YAP/TEAD, reduced the expression of the downstream pathway proteins CCN1, CTGF and CARP, promoted the reduction of mitochondrial membrane potential in 92.1 cells, and induced apoptosis and cell cycle arrest in 92.1 cells, which had a synergistic effect with dacarbazine. Moreover, the integration of molecular dynamics simulations with energy analysis identified (R)-isomontanol as a promising inhibitor. The identification of key hydrophobic residues is of paramount importance, as these residues have been shown to be crucial for TEAD-ligand interactions. Furthermore, these residues have been demonstrated to exhibit both high binding stability and the strongest pharmacological potential when compared to the other investigated compounds. This provides valuable insights for the design of more potent TEAD inhibitors in future studies. These findings provide new ideas and drugs for the treatment of UM. Bridging the gap in research on the interaction of Astragalus with transcription factors. Biological sciences/Biochemistry Biological sciences/Cancer Biological sciences/Computational biology and bioinformatics Biological sciences/Drug discovery uveal melanoma synergistic effect TEAD astragalus Full Text Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Revision Version 1 posted Editorial decision: Revision requested 14 May, 2026 Reviews received at journal 25 Apr, 2026 Reviewers agreed at journal 23 Apr, 2026 Reviewers invited by journal 17 Apr, 2026 Editor assigned by journal 14 Apr, 2026 Editor invited by journal 16 Jan, 2026 Submission checks completed at journal 14 Jan, 2026 First submitted to journal 14 Jan, 2026 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-8314542","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":628457696,"identity":"ee89b375-7a76-4b40-8b7c-681a130e5a8d","order_by":0,"name":"Yuemei 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Astragalus, as a medicinal and edible herbs, may play a role in the treatment of cancer by combining different chemotherapeutic agents. In this study, we first found that Astragalus can be combined with dacarbazine for the treatment of uveal melanoma using a hormonal mouse model and determined that the transcription factor TEAD may be one of the reasons for the reduced sensitivity of uveal melanoma to dacarbazine chemotherapy. Subsequently, using a multidisciplinary approach of computer-aided drug design combined with cellular experiments and molecular pairing, we found that RISO, a compound in Astragalus, stabilised the binding of YAP/TEAD, reduced the expression of the downstream pathway proteins CCN1, CTGF and CARP, promoted the reduction of mitochondrial membrane potential in 92.1 cells, and induced apoptosis and cell cycle arrest in 92.1 cells, which had a synergistic effect with dacarbazine. 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