Corin: a dual inhibitor for KDM1A/HDAC1, suppresses hepatocellular carcinoma by triggering cuproptosis

Hepatocellular carcinoma (HCC) accounts for more than 90% of all liver cases and often responds poorly to conventional treatment modalities, including multi-kinase inhibitors and immune checkpoint inhibitors. Therefore, it is urgent to develop novel therapeutic options for HCC. In this study, we conducted high-throughput screening of histone demethylase inhibitors for HCC treatment. Among the inhibitors examined, Corin significantly suppressed the growth and proliferation of two HCC cell lines, HepG2 and Hep3B cells without affecting non-cancerous cells. Based on the targets of Corin, we identified HDAC1/KDM1A dual-positive HCC as a novel subtype of HCC. Transcriptome profiling indicated that this novel subtype possessed rapid proliferation and high DNA damage repair capacity. Additionally, Corin treatment upregulated FDX1 expression to trigger Cuproptosis, which suppressed HCC proliferation. Conclusively, Corin possesses potential application as a novel and effective therapeutic option for HCC that simultaneously inhibits KDM1A and HDAC1 expression.