Imipramine Reverses Sorafenib Resistance in Hepatocellular Carcinoma by Targeting the BLOC1S5/FOXO1 Signaling Axis

Liver cancer, particularly hepatocellular carcinoma (HCC), is among the leading causes of cancer-related mortality worldwide, with drug resistance posing a significant therapeutic challenge. Therefore, overcoming this barrier is a critical step toward improving survival outcomes in patients with drug-resistant disease. Here, we demonstrate that the antidepressant imipramine effectively inhibits tumor growth in vitro and in vivo. Notably, imipramine enhances the anticancer efficacy of sorafenib, resulting in an additive suppression of tumor growth and cell migration. Moreover, imipramine treatment restores sensitivity in sorafenib-resistant hepatoma cells. RNA-sequencing analysis identified increased expression of BLOC1S5 in sorafenib-resistant cells compared to their parental counterparts. Functional assays indicated that overexpression of BLOC1S5 promotes tumor sphere formation, cell migration, sorafenib resistance, and metastasis through suppression of FOXO1. Imipramine treatment significantly reduced BLOC1S5 expression while inducing FOXO1 expression. Crucially, the inhibitory effect of imipramine on cell migration was reversed by BLOC1S5 overexpression, indicating that imipramine acts, at least in part, by suppressing this protein. Clinically, elevated BLOC1S5 expression correlated with poor prognosis, whereas higher FOXO1 levels were associated with favorable outcomes in HCC patients. Collectively, these results highlight the repurposing of imipramine as a promising therapeutic strategy to sensitize HCC cells to sorafenib via modulation of the BLOC1S5/FOXO1 signaling axis.