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 chemopreventive strategies, we identified Aripiprazole, an oral atypical antipsychotic, as a candidate for HCC chemoprevention. Transcriptomic analyses of clinical liver tissues showed an association of Aripiprazole target gene expression with fibrotic liver diseases severity. In a rat model of MASH-induced HCC induced by choline-deficient L-amino acid-defined and high-fat diet, Aripiprazole prevented liver disease progression toward HCC development by modulating fibrogenesis, inflammation, and immunity-related pathways. Moreover, Aripiprazole exhibits an antifibrotic effect and reverses the high-risk status of the prognosis liver signature (PLS), a signature associated with disease progression and HCC risk in patients, in multiple human liver cell-based models. Mechanistic studies demonstrated that Aripiprazole exerts antifibrogenic, and anti-proliferative effects via suppression of TGF-beta, NF-kB, cMet-ERK, and PI3K/AKT signaling in liver epithelial cells and myofibroblasts. Finaly, perturbation studies in patient-derived cell lines and patient-derived tumorspheroid system showed that Aripiprazole has a direct anticancer effect, by modulating the tumor microenvironment and suppressing tumor cell survival and invasion. Collectively, these findings suggest that treatment with aripiprazole is a clinically relevant approach for HCC chemoprevention.