Abstract
Hepatocellular carcinoma (HCC) remains a therapeutic challenge due to the limited efficacy of current systemic therapies. To identify potential therapeutic approaches, computational analysis of HCC datasets and drug screening were integrated, leading to the repurposing of hematological malignancy drug selinexor (an XPO1 inhibitor) for HCC treatment. Functional studies revealed that XPO1 inhibition triggers oxidative stress and cell cycle arrest in HCC cells through nuclear sequestration of NCOR1, disrupting redox homeostasis through FOXK1-dependent transcriptional activation of genes associated with reactive oxygen species (ROS). A genome-wide CRISPR-Cas9 screen further identified the KEAP1-NRF2 axis as a key determinant of sensitivity to XPO1 inhibition. Furthermore, high-throughput compound screening demonstrated that disulfiram, a clinically used aldehyde dehydrogenase inhibitor, synergizes with XPO1 inhibitor through exacerbation of ROS accumulation. Collectively, these findings demonstrate the therapeutic repurposing of selinexor for HCC while uncovering its mechanism of action, establishing a predictive biomarker, and proposing an immediately translatable combination therapy.