Atorvastatin promotes lipid catabolism in colorectal cancer via FDFT1‒mediated inhibition of the PI3K/AKT pathway

Abstract As a hydroxymethylglutaryl‒coenzyme A reductase (HMGCR) inhibitors, atorvastatin (ATST) has garnered widespread attention because of its antitumor effects. However, its specific mechanism of action remains incompletely understood. In our study, ATST was found to inhibit AOM/DSS‒induced colorectal cancer (CRC) progression in mice. Mechanistically, by inhibiting HMGCR and depleting cellular cholesterol, ATST activates the SREBP2‒FDFT1 axis. This in turn inhibits the PI3K/AKT pathway, inducing endoplasmic reticulum (ER) stress and autophagy while concurrently promoting lipid catabolism to drive ferroptosis. This study elucidates the mechanism through which ATST regulates lipid catabolism to influence CRC progression, providing a new direction for CRC therapy.