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

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Colorectal cancer (CRC) drug resistance necessitates novel therapeutic approaches.
• Arteannuin B, a sesquiterpene lactone from Artemisia annua, is explored for its anti-cancer potential.

Purpose of the Study:

• To investigate if arteannuin B induces ferroptosis in colorectal cancer cells.
• To elucidate the molecular mechanisms underlying arteannuin B's effects on CRC.

Main Methods:

• Cell viability assays (MTT) and xenograft models assessed anti-CRC effects.
• Proteomics, ROS, lipid peroxidation, Fe²⁺, GPX4, and mitochondrial morphology evaluated ferroptosis.
• Mevalonate pathway analysis involved western blotting and metabolite quantification.
• GDF15's role was studied using knockdown and overexpression cell lines.

Main Results:

• Arteannuin B demonstrated significant anti-CRC activity in vitro and in vivo.
• Proteomics revealed arteannuin B impacts the mevalonate pathway and ferroptosis, upregulating GDF15.
• Arteannuin B increased oxidative stress markers and iron, decreased GPX4, and altered mitochondrial morphology.
• Inhibition of mevalonate pathway enzymes (HMGCS1) and downstream metabolites (squalene, CoQ10, cholesterol) was observed.
• GDF15 knockdown attenuated arteannuin B's effects on the mevalonate pathway, GPX4, and CRC cell sensitivity.

Conclusions:

• Arteannuin B induces ferroptosis-like cell death in CRC cells and inhibits tumor growth by targeting the mevalonate pathway.
• GDF15 plays a crucial role in mediating arteannuin B's effects on HMGCS1, GPX4, and ferroptosis sensitivity in CRC.