Therapeutic Perturbation of Liver and Bile Duct Cancer through Targeted Inhibition of FSP1 and GCS Induced Ferroptosis

Triggering ferroptosis has recently been demonstrated to be a promising approach for cancer treatment. However, the application of current ferroptosis inducers, such as GPX4 inhibitors, was rather limited due to their pharmaceutical or safety issues, which evoking the discovery of new favorable candidates. In this study, we took advantage of a phenotypic screening strategy and discovered (20S)-Protopanaxatriol (hereafter as (20)S-APPT), a derivative of ginsenosides, as a novel ferroptosis inducer both in vitro and in vivo, with desirable safety in particular. Mechanistic investigations revealed that (20)S-APPT induces ferroptosis by targeting plasma-membrane localized CoQ10 oxidoreductase FSP1. Upon FSP1 inhibition, oxidation of arachidonic acid in an ACSL4 dependent way as well as reactive oxygen species produced by mitochondrial oxidative stress are both involved to boost the process of ferroptosis. Intriguingly, we firstly uncovered that inhibition of FSP1 alone is sufficient to induce ferroptotic cell death in a subset of liver and bile duct cancer cells. Furthermore, we unexpectedly found that only the addition of GCS inhibitor BSO, which attenuates intracellular GSH, exerts synergistic effect to induce ferroptosis with FSP1 inhibitors in rest non-responsive cancer cells, while sparing normal cell counterparts intact. Overall, our work helped to gain insights into a new ferroptotic role of FSP1 and further proposed that co-targeting FSP1 and GCS is a hopeful and safe strategy to combat liver and bile duct cancer through triggering ferroptosis, which might facilitate to pave a new way for drug development and further clinical therapeutic intervention in the future.