{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,4,18]],"date-time":"2026-04-18T13:45:23Z","timestamp":1776519923585,"version":"3.51.2"},"posted":{"date-parts":[[2026,3,10]]},"group-title":"Cancer Biology","reference-count":51,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T00:00:00Z","timestamp":1773100800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nd\/4.0\/"}],"funder":[{"name":"CJ Huang Foundation"},{"name":"Mavis and CH Fong"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, underscoring the urgent need for effective therapies. The FDA-approved anthelmintic, niclosamide, is a promising repurposed drug candidate for HCC; however, its clinical application in solid tumors is hampered by poor aqueous solubility and resulting low bioavailability.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We designed and screened eight novel niclosamide prodrug candidates for solubility, stability, and anti-proliferative activity in HCC cell lines. The lead compound, SSL-0024, was evaluated for pharmacokinetics and anti-tumor efficacy in an orthotopic patient-derived xenograft (PDX) model, and for cytotoxicity in patient-derived organoids (PDOs). Mechanistic studies assessed AKT\u2013mTOR\u2013STAT3 and other related signaling pathways.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    The O-sulfate derivative, SSL-0024, demonstrated improved solubility and pH stability, and a sustained release of niclosamide over \u223c48 h. Once-daily oral administration of SSL-0024 (100 mg\/kg) achieved \u223c60% tumor growth inhibition in PDX models at \u223c46.8% of the niclosamide ethanolamine dose, with minimal toxicity. It also induced significantly greater cytotoxicity than sorafenib (\n                    <jats:italic>p&lt;0.05<\/jats:italic>\n                    ) in the PDO. Mechanistically, SSL-0024 suppressed major oncogenic pathways including AKT\u2013mTOR\u2013STAT3, RAF, and Wnt\/\u03b2-catenin.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>SSL-0024 overcomes key pharmacokinetic limitations of niclosamide while maintaining potent anti-tumor activity, supporting its further development as an orally bioavailable therapeutic candidate for HCC.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.03.06.710248","type":"posted-content","created":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T20:00:09Z","timestamp":1773172809000},"source":"Crossref","is-referenced-by-count":0,"title":["A Novel Niclosamide Sulfate Prodrug with Enhanced Bioavailability Suppresses Hepatocellular Carcinoma via Inhibition of Multiple Signaling Pathways"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3064-2189","authenticated-orcid":false,"given":"Mingdian","family":"Tan","sequence":"first","affiliation":[{"name":"Department of Surgery, School of Medicine, Asian Liver Center, Stanford, CA 94305, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steve","family":"Schow","sequence":"additional","affiliation":[{"name":"Department of Chemical and Systems Biology Operations, Stanford University School of Medicine"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6592-9262","authenticated-orcid":false,"given":"Yi","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Surgery, School of Medicine, Asian Liver Center, Stanford, CA 94305, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert","family":"Lum","sequence":"additional","affiliation":[{"name":"RTL Consulting Group LLC"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6326-8723","authenticated-orcid":false,"given":"Dawiyat","family":"Massoudi","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University, CA 94305, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8819-7511","authenticated-orcid":false,"given":"Renumathy","family":"Dhanasekaran","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University, CA 94305, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3108-086X","authenticated-orcid":false,"given":"Samuel","family":"So","sequence":"additional","affiliation":[{"name":"Department of Surgery, School of Medicine, Asian Liver Center, Stanford, CA 94305, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3282-4894","authenticated-orcid":false,"given":"Mei-Sze","family":"Chua","sequence":"additional","affiliation":[{"name":"Department of Surgery, School of Medicine, Asian Liver Center, Stanford, CA 94305, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026041806150865000_2026.03.06.710248v2.1","doi-asserted-by":"crossref","unstructured":"Singh, S.P. , Madke, T. & Chand, P . 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