Atorvastatin as a pleiotropic anticancer agent: mechanisms, evidence, and therapeutic repurposing potential

Cancer remains a leading cause of global mortality, with incidence and mortality rates rising annually. Atorvastatin, a widely used statin, primarily functions by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in the mevalonate pathway, thereby lowering cholesterol. Accumulating preclinical and clinical evidence suggests that ATV possesses significant anticancer properties beyond its lipid-lowering effects, positioning it as a promising candidate for adjunctive cancer therapy. The anticancer efficacy of ATV stems fundamentally from its disruption of the mevalonate pathway, which impedes the critical isoprenylation of small GTPases (e.g., Ras, Rho). This inhibition cascades into multifaceted antitumor activities, including the induction of apoptosis and autophagy, dysregulation of the cell cycle, suppression of proliferation, migration, and invasion. ATV further modulates key oncogenic signaling pathways and exhibits potent anti-inflammatory and antioxidant effects within the tumor microenvironment. Crucially, evidence demonstrates that integrating ATV into multimodality regimens-such as alongside immune checkpoint inhibitors and metabolic modulators-significantly improves survival outcomes in patients, substantiating its clinical translational potential. However, a comprehensive and systematic evaluation of its pleiotropic anticancer mechanisms and therapeutic potential is lacking. This review aims to fill this gap by systematically summarizing the efficacy and molecular mechanisms of ATV across various malignancies, alongside its cytoprotective effects on normal tissues. The challenges and future directions for its clinical translation in oncology are also critically discussed.