Arteannuin B Induces Ferroptosis in Colorectal Cancer Cells via GDF15/HMGCS1/GPX4 Axis.

PURPOSE: Drug resistance in colorectal cancer (CRC) necessitates novel therapeutic strategies. This study investigated whether arteannuin B, a sesquiterpene lactone from Artemisia annua, induces ferroptosis in CRC cells and elucidated the underlying molecular mechanism.

METHODS

Anti-CRC effects were assessed via MTT assays and xenograft models. Proteomics identified differentially expressed proteins. Arteannuin B-induced ferroptosis was confirmed by measuring reactive oxygen species (ROS), lipid peroxidation, Fe²⁺ content, glutathione peroxidase 4 (GPX4) expression, and mitochondrial morphology. Mevalonate pathway regulation was evaluated by western blotting, dual-luciferase assay, and quantification of squalene, coenzyme Q10 (CoQ10), and cholesterol. The role of growth differentiation factor 15 (GDF15) was validated using shRNA knockdown and overexpression DLD-1 cells in vitro and in vivo.

RESULTS

Arteannuin B showed significant anti-colorectal cancer activity both in vitro and in vivo. The proteomic analysis demonstrated that arteannuin B affected the mevalonate pathway and ferroptosis in DLD-1 cells, and strongly upregulated the expression of GDF15. Arteannuin B increased ROS, lipid peroxidation, malondialdehyde, and iron while decreasing GPX4 expression and causing mitochondrial shrinkage. Arteannuin B inhibited mevalonate pathway enzymes, particularly 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1), reducing squalene, CoQ10, and cholesterol. The knockdown of GDF15 weakened the inhibitory effect of arteannuin B on the mevalonate pathway and GPX4, and reduced the sensitivity of CRC cells to arteannuin B both in vitro and in vivo.

CONCLUSION

Arteannuin B triggers ferroptosis-like cell death in CRC cells and suppresses xenograft growth, in association with inhibition of the mevalonate pathway. GDF15 contributes to arteannuin B-mediated suppression of HMGCS1 and GPX4 and to ferroptosis sensitivity.