A glycosylated naphthalimide conjugate preferentially accumulates in metastatic hepatocellular carcinoma as ROS-mediated mitochondrial-targeted antimetastatic agent

For patients with hepatocellular carcinoma (HCC), recurrence and metastasis lead to approximately 90% deaths, even after various standard therapies, indicating the need for novel therapies and antimetastatic drugs. Recently, mitochondrial dysfunction has been shown to be closely associated with HCC recurrence and metastasis. Herein, a novel glycosylated naphthalimide conjugate <b>4a</b> was explored to target HCC and HCC metastasis by inducing ROS-mediated mitochondrial metabolic programs in HCC, remarkably improving the efficacy of amonafide and prolonging the survival of mice. Mechanistically, <b>4a</b>, as a potential fluorescent chemical probe, could target mitochondria, which is completely different from amonafide. Preliminary investigation into the mechanism of <b>4a</b> indicates that it localizes in the mitochondria and selectively causes reactive oxygen species (ROS) overproduction in HCC instead of the matched normal liver cells, leading to HCC cell apoptosis and migration inhibition <i>via</i> multiple ROS-mediated signaling pathways. In addition to exposing a previously undefined mitochondrial metabolic program in HCC, our study further illuminates an unrecognized naphthalimide-based tumor therapeutic strategy to prolong the life of terminal HCC in a completely new field.