Niclosamide Prodrug Enhances Oral Bioavailability and Targets Vasorin-TGFβ Signaling in Hepatocellular Carcinoma

BackgroundHepatocellular carcinoma (HCC) ranks third in cancer-related deaths worldwide, with limited therapeutic options. While niclosamide (NIC) has shown potential for repurposing in HCC, its poor water solubility and low bioavailability limit its efficacy, and its mechanisms of action are not yet fully elucidated. MethodsWe designed a water-soluble NIC prodrug (NIC-PS) and evaluated its efficacy through in vitro and in vivo studies, including pharmacokinetic (PK) and pharmacodynamic (PD) assays, HCC patient-derived xenograft (PDX) models were applied in two independent experiments, vasorin (VASN) knockout models, and combination treatments with NIC-PS and sorafenib or anti-PD-L1 antibody. Bioinformatic analyses and western blotting were used to investigate NIC-PSs target, VASN, and related signaling pathways. ResultsNIC-PS exhibited a ten-fold increase in oral bioavailability and reduced tumor volume by over 75% in HCC PDX models. NIC-PS directly binds and suppresses VASN, suppressing TGF{beta} signaling and reducing SMAD2/3 phosphorylation. VASN inhibition led to a 50% tumor reduction, and NIC-PS enhanced responses to sorafenib and anti-PD-L1 therapy. ConclusionsNIC-PS, equal to 36% of NIC in molecular weight, offers improved bioavailability, efficacy, and a novel mechanism of action in targeting VASN, showing promise for HCC treatment alone or in combination therapy.