Targeting the LY6H-PI3K/AKT Autophagy Axis Suppresses HCC Malignancy and Reveals a Druggable Vulnerability

Targeting the LY6H-PI3K/AKT Autophagy Axis Suppresses HCC Malignancy and Reveals a Druggable Vulnerability | 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 Targeting the LY6H-PI3K/AKT Autophagy Axis Suppresses HCC Malignancy and Reveals a Druggable Vulnerability Aimin Huang, Fei Wei, Jie Wang, Ye Cheng, Caiyan Chen, Yong Wu, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7392770/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 11 You are reading this latest preprint version Abstract Hepatocellular carcinoma (HCC) is a highly lethal malignancy worldwide, with its initiation and progression closely tied to dysregulated autophagy. Lymphocyte antigen 6 family member H (LY6H), a glycosylphosphatidylinositol-anchored protein, is aberrantly expressed in multiple cancers, yet its functions and mechanisms in HCC remain undefined. Here, we demonstrate that LY6H is markedly upregulated in HCC specimens and that elevated LY6H correlates with poorer patient survival. Transcriptome analysis links LY6H expression to enhanced autophagic activity in HCC cells. Mechanistically, LY6H directly binds the p85 subunit of PI3K, promoting its phosphorylation at Tyr467, thereby activating the PI3K/AKT pathway and driving autophagy. Both in vitro and in vivo assays confirm that LY6H fosters autophagy-dependent proliferation of HCC cells. Importantly, we identify NSC243928 as a small-molecule inhibitor of LY6H, which effectively abrogates its tumor-promoting functions. Immunohistochemical studies reveal positive correlations among LY6H, ATG3, Beclin1, PI3K, and AKT expression in HCC tissues, with their co-overexpression predicting adverse prognosis. This work uncovers the critical LY6H–p-PI3K axis in HCC autophagy regulation and introduces a promising therapeutic candidate for targeting LY6H in liver cancer. Health sciences/Diseases/Cancer/Gastrointestinal cancer/Liver cancer Biological sciences/Cancer/Gastrointestinal cancer/Liver cancer LY6H (Lymphocyte antigen 6 family member H) Hepatocellular carcinoma (HCC) Autophagy PI3K/AKT pathway NSC243928 Full Text Additional Declarations (Not answered) Supplementary Files Originalwesternblots.docx Original western blots Supplementaryinformation.docx Supplementary information Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: revise 05 Dec, 2025 Review # 3 received at journal 06 Nov, 2025 Reviewer # 3 agreed at journal 24 Oct, 2025 Review # 2 received at journal 15 Oct, 2025 Reviewer # 2 agreed at journal 03 Oct, 2025 Reviewer # 1 agreed at journal 17 Sep, 2025 Reviewers invited by journal 17 Sep, 2025 Submission checks completed at journal 21 Aug, 2025 First submitted to journal 20 Aug, 2025 Unknown event 18 Aug, 2025 Editor assigned by journal 17 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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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-7392770","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":503568587,"identity":"1f3cf886-5dbb-43c7-bcf3-6c962683d55b","order_by":0,"name":"Aimin 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