Dihydrochelerythrine Induced Ferroptosis via Glutathione Peroxidase 4 Downregulation in Prostate Cancer Cells.

The purpose of this study was to elucidate the role of dihydrochelerythrine (DHC) in prostate cancer and to explore its targets in DU145 and PC3 cells. DHC significantly inhibited the growth of both cell lines. RNA-sequencing analysis revealed that ferroptosis-related genes, including glutathione peroxidase 4 (GPX4) and light chain 3, were significantly downregulated in DHC-treated DU145 cells. Molecular docking studies demonstrated significant interactions between DHC and the GPX4 protein, with a binding energy of -9.01 kcal/mol. Furthermore, GPX4 mRNA expression was significantly upregulated in 497 prostate tumor samples compared to normal tissue in the Cancer Genome Atlas prostate adenocarcinoma dataset. DHC markedly induced ferroptosis in DU145 and PC3 cells by suppressing GPX4 expression, increasing mitochondrial membrane density, and reducing/vanishing mitochondrial cristae, leading to lipid reactive oxygen species production. Treatment with Ferrostatin-1 partially rescued the cell viability reduced by DHC. Collectively, these findings suggest that DHC may be a potential agent for inducing ferroptosis in prostate cancer cells by decreasing GPX4 expression.