Chemoprevention of hepatocellular carcinoma by next-generation antipsychotic aripiprazole

Hepatocellular carcinoma (HCC) is the most common form of liver cancer and is a major global health burden, ranking sixth in incidence and third in cancer-related mortality. Despite therapeutic advances, treatment options for advanced liver disease and HCC are limited and strategies to prevent HCC development are lacking. To address the urgent need for preventive strategies, we identified aripiprazole, an oral atypical antipsychotic, as a candidate for HCC chemoprevention. Analyses of clinical liver tissues showed that aripiprazole targets are expressed in different liver cell compartments including fibroblasts, macrophages and epithelial cancer cells, and that target gene expression is associated with fibrotic liver diseases and HCC. In a rat model of MASH-induced HCC induced by choline-deficient L-amino acid-defined and high-fat diet, aripiprazole prevents liver disease progression and HCC development by modulating fibrogenesis related pathways and inflammation. Mechanistically, aripiprazole exerts antifibrogenic and anti-inflammatory effects by modulating the phenotype of liver fibroblasts and macrophages. Moreover, perturbation studies in cancer cell models showed that aripiprazole prevents tumor initiation and reduces cell proliferation via inhibition of the cMET and ERK pathways and perturbation of mitochondrial functions. Finally, treatment of patient-derived tumorspheroids demonstrated that aripiprazole modulates immune responses in the tumor microenvironment. Collectively, these findings suggest that treatment with aripiprazole is a clinically relevant approach for HCC chemoprevention.