“Small molecule-driven ERK activation is known to induce autophagy and ferroptosis in cancer cells. Herein the effect of cannabidiol (CBD), a phytochemical derived from Cannabis sativa, on ERK-driven autophagy and ferroptosis has been demonstrated in glioblastoma (GBM) cells (U87 and U373 cells).

CBD imparted significant cytotoxicity in GBM cells, induced activation of ERK (not JNK and p38), and increased intracellular reactive oxygen species (ROS) levels. It increased the autophagy-related proteins such as LC3 II, Atg7, and Beclin-1 and modulated the expression of ferroptosis-related proteins such as glutathione peroxidase 4 (GPX4), SLC7A11, and TFRC. CBD significantly elevated the endoplasmic reticulum stress, ROS, and iron load, and decreased GSH levels. Inhibitors of autophagy (3-MA) and ferroptosis (Fer-1) had a marginal effect on CBD-induced autophagy/ferroptosis. Treatment with N-acetyl-cysteine (antioxidant) or PD98059 (ERK inhibitor) partly reverted the CBD-induced autophagy/ferroptosis by decreasing the activation of ERK and the production of ROS.

Overall, CBD induced autophagy and ferroptosis through the activation of ERK and generation of ROS in GBM cells.”

https://pubmed.ncbi.nlm.nih.gov/38583854/

“In this study, we investigated the anti-cancer effect of CBD. CBD activated ROS production and ERK pathway and modulated the expression of proteins related to autophagy and ferroptosis. Additionally, CBD suppressed the activity of SLC7A11, a component of the System Xc-cystine/glutamate receptor, and enhanced the expression of TFRC, an iron ion channel. Through these mechanisms, our study provides evidence that CBD stimulates both autophagy and ferroptosis in GBM cells”

https://www.sciencedirect.com/science/article/abs/pii/S0009279724001418?via%3Dihub