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We performed a head-to-head comparison of N-acetylgalactosamine (GalNAc)-conjugated small interfering RNA (siRNA)-mediated inhibition of five genes (CDK1, PD-L1, CTNNB1, SMYD3, ANLN) to prevent cancer in four distinct autochthonous HCC mouse models. siRNA targeting Cdk1 and Anln (siCdk1 and siAnln, respectively) increased overall survival in the CTNNB1\/MYC hydrodynamic transfection (HDT) model, in which HCC formation is driven by oncogenes. Both long-term and transient dosing of siCtnnb1 or siAnln prevented cancer development in the NRASG12V\/shp53-driven HDT model. siCdk1 and siAnln prevented cancer in a diethylnitrosamine\/phenobarbital model, in which tumor formation is driven by mutagenesis and chemical injury. Moreover, siCtnnb1 and siAnln decreased cancer development in a metabolic dysfunction-associated steatohepatitis (MASH) model driven by a Western diet and carbon tetrachloride (CCl4). Given that the use of siAnln was effective in several models, we validated Anln effects using Cre-lox and found that histologic features of MASH and HCC development were independently reduced. This demonstrates that siRNAs are safe and effective in preventing HCC in a large panel of preclinical cancer models, and identifies ANLN as an effective chemoprevention target.<\/jats:p>","DOI":"10.1242\/dmm.052370","type":"journal-article","created":{"date-parts":[[2025,7,24]],"date-time":"2025-07-24T10:06:33Z","timestamp":1753351593000},"source":"Crossref","is-referenced-by-count":5,"title":["Chemoprevention of hepatocellular carcinoma using N-acetylgalactosamine-conjugated siRNAs"],"prefix":"10.1242","volume":"18","author":[{"given":"Gianna","family":"Maggiore","sequence":"first","affiliation":[{"name":"Children's Research Institute 1 , Departments of Pediatrics and Internal Medicine , , Dallas, TX 75390 ,","place":["USA"]},{"name":"Center for Regenerative Science and Medicine, Simmons Comprehensive Cancer Center, Children's Research Institute Mouse Genome Engineering Core, University of Texas Southwestern Medical Center 1 , Departments of Pediatrics and Internal Medicine , , 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