Integrated analysis reveals FOXA1 and Ku70/Ku80 as direct targets of ivermectin in prostate cancer

Ivermectin is a widely used antiparasitic drug and shows promising anticancer activity in various cancer types. Although multiple signaling pathways modulated by ivermectin have been identified, few studies have focused on the exact target of ivermectin. Herein, we report the pharmacological effects and direct targets of ivermectin in prostate cancer (PCa). Ivermectin caused G0/G1 arrest, induced cell apoptosis, DNA damage, and decreased androgen receptor (AR) signaling in PCa cells. Using integrated omics profiling, including RNA-seq and thermal proteome profiling, we found that the forkhead box protein A1 (FOXA1) and non-homologous end joining (NHEJ) repair executer Ku70/Ku80 were the direct targets of ivermectin. The binding of ivermectin and FOXA1 reduced the chromatin accessibility of AR and the G0/G1 cell cycle regulator E2F1, leading to cell proliferation inhibition. The binding of ivermectin and Ku70/Ku80 impaired the NHEJ repair ability. Cooperating with the downregulation of homologous recombination repair after AR inhibition, ivermectin triggered synthetic lethality. Our findings demonstrate the anticancer effect of ivermectin in prostate cancer, indicating that its use may be a new therapeutic approach for PCa.