Simvastatin induces ferroptosis of colorectal cancer cells and is associated with mevalonate pathway inhibition
Year: 2025
Type: article
Abstract: 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.
Authors: Shihua Zhang, Kejin Li, Yan Chen, Yusong Liu, Lin Wang, Limao Xu
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $1,400
OpenAlex ID: W7117355685