Novel meroterpene-like compounds inhibit ferroptosis through Fe2+ chelation

Colorectal cancer (CRC) is the third most common type of cancer in the world. It is characterized by complex crosstalk between various signaling pathways, as a result of which it is highly challenging to identify optimal therapeutic targets and design treatment strategies. In this study, we tested the effect of 700 compounds on the CRC cell line HT-29 by using the sulforhodamine B assay and screened out 17 compounds that exhibited high toxicity (indicated by an inhibition rate of ≥75 % when applied at a concentration of 10 µM) against the HT-29 cell line. Next, we investigated the mechanisms underlying the effects of these 17 highly toxic compounds. The results of ferroptosis analysis and electron microscopy showed that compounds 575 and 578 were able to significantly reverse RSL3-induced increase in ferroptosis, while compound 580 had a less pronounced ferroptosis-regulating effect. In subsequent experiments, western blotting showed that compounds 575, 578, and 580, which belong to a class of meroterpene-like compounds that affect ferroptosis, do not induce autophagy or apoptosis in the CRC cell line. Instead, Fe²⁺ chelation experiments showed that these three compounds can serve as iron chelators by chelating Fe²⁺ at a 1:1 (chelator: Fe²⁺) ratio. Specifically, the aldehyde and hydroxyl groups of the benzene ring in these compounds may chelate Fe²⁺, thus reducing Fe²⁺ levels in cells and inhibiting ferroptosis. These results indicate that these novel meroterpene-like compounds are potential therapeutic small-molecule candidates for targeting ferroptosis in tumors.