Simvastatin induces ferroptosis of colorectal cancer cells and is associated with mevalonate pathway inhibition

This study aimed to elucidate the molecular mechanism by which simvastatin promotes ferroptosis in colorectal cancer cells, focusing on its targeting of HMGCR, suggesting that simvastatin-induced ferroptosis is associated with mevalonate pathway suppression. Cell proliferation was evaluated after exposure to various concentrations of simvastatin. The expression of GPX4 and HMGCR was quantified using RT-qPCR and western blotting following treatment with simvastatin alone or combined with the ferroptosis inhibitor ferrostatin-1 (Fer-1). Apoptosis was analyzed by flow cytometry. In addition, intracellular reactive oxygen species (ROS), malondialdehyde (MDA), and ferrous iron (Fe 2+ ) levels were determined to assess metabolic alterations induced by simvastatin. Treatment with 20 μM simvastatin for 72 h significantly inhibited the proliferation of HCT116 and HCT15 cells, and reduced both mRNA and protein levels of GPX4 and HMGCR. Simvastatin also increased overall cell death, as detected by Annexin V/PI staining, and the rescue by Fer-1 supports ferroptosis as the primary mechanism. Co-treatment with Fer-1 attenuated these effects by restoring GPX4 expression and reducing apoptosis, ROS, MDA, and Fe 2+ levels. Simvastatin induces ferroptosis in HCT116 and HCT15 cells by enhancing lipid peroxidation and oxidative stress. The inhibitory influence of Fer-1 on these changes underscores the pivotal involvement of ferroptosis in simvastatin's antitumor effect. Overall, the results highlight simvastatin as a potential therapeutic option for colorectal cancer management.