Ferropotsis is among the most important mechanisms of
cancer suppression, which could be harnessed for
cancer therapy. However, no natural small-molecule compounds with
cancer inhibitory activity have been identified to date. In the present study, we reported the discovery of a novel ferroptosis inducer,
talaroconvolutin A (TalaA), and the underlying molecular mechanism. We discovered that TalaA killed
colorectal cancer cells in dose-dependent and time-dependent manners. Interestingly, TalaA did not induce apoptosis, but strongly triggered ferroptosis. Notably, TalaA was significantly more effective than
erastin (a well-known ferroptosis inducer) in suppressing
colorectal cancer cells via ferroptosis. We revealed a dual mechanism of TalaA' action against
cancer. On the one hand, TalaA considerably increased
reactive oxygen species levels to a certain threshold, the exceeding of which induced ferroptosis. On the other hand, this compound downregulated the expression of the channel
protein solute carrier family 7 member 11 (SLC7A11) but upregulated arachidonate
lipoxygenase 3 (ALOXE3), promoting ferroptosis. Furthermore, in vivo experiments in mice evidenced that TalaA effectively suppressed the growth of xenografted
colorectal cancer cells without obvious liver and kidney toxicities. The findings of this study indicated that TalaA could be a new potential powerful
drug candidate for
colorectal cancer therapy due to its outstanding ability to kill
colorectal cancer cells via ferroptosis induction.