Dracorhodin perochlorate sensitizes colorectal cancer to ferroptosis by activating HMOX1 and inhibiting the SLC7A11/GPX4 axis

Background: Ferroptosis, an iron-dependent form of cell death mediated by lipid peroxidation, plays a critical role in tumor progression. The natural small molecule compound dracorhodin perchlorate (DP) exhibits antitumor activity, but its effects on colorectal cancer (CRC) and the underlying mechanisms remain unclear. Objective: This study aimed to elucidate the role and mechanism of DP in CRC development and ferroptosis promotion. Methods: Using RNA-Seq, molecular docking and molecular dynamics simulation, we observed ferroptosis levels and expression of HMOX1, SLC7A11, and GPX4 in CRC cells treated with DP. We also examined the impact of modulating HMOX1, SLC7A11, and GPX4 on DP-induced ferroptosis and antitumor effects. Results: DP inhibited various malignant behaviors of CRC cells and induced ferroptosis. Mechanistically, RNA-Seq, molecular dynamics simulations, and molecular docking studies have collectively confirmed that DP directly binds to the HO-1 molecule, thereby upregulating HO-1 expression and inducing iron overload. Additionally, DP downregulates the expression of SLC7A11 and GPX4, collectively promoting the occurrence of ferroptosis in CRC cells. The HO-1 inhibitor ZnPP and SLC7A11 overexpression significantly inhibited the antitumor activity and ferroptosis induced by DP. Hemin and ferroptosis inducers enhanced its therapeutic effectiveness. DP safely suppressed subcutaneous tumor growth and exhibited synergistic effects with cisplatin both in vitro and in vivo. HMOX1 knockdown weakened the ferroptosis induced by DP in CRC. Conclusions: The findings strongly support the activation of HMOX1 by DP, downregulation of the SLC7A11/ GSH/GPX4 axis, and induction of ferroptosis in CRC cells. DP inhibited CRC progression and acted synergistically when combined with cisplatin. Our research provides a scientific basis for the use of DP in the treatment of CRC and offers new insights into the application of traditional Chinese medicine in the fight against CRC.