Microglia as a key mediator in rosuvastatin-associated cognitive impairment

Background Hydroxymethylglutaryl-coenzyme A (HMGCR) inhibitors, known as statins, as first-line lipid-lowering therapies for cardiovascular diseases. Despite their widespread use, concerns persist regarding potential cognitive adverse effects, although a definitive causal relationship remains elusive. Methods To investigate the underlying mechanisms, this study integrated network toxicology, in vitro experiments, public RNA-sequencing data, computational simulations, and Mendelian randomization analysis. Rosuvastatin was chosen as a representative statin, with human as the focused species and the HMC3 human microglial cell line as the in vitro model. Results Network toxicology initially identified microglia as a critically involved cell type. A multi-method approach then demonstrated that rosuvastatin alters microglial functions—including cell viability, migration, phagocytosis, and inflammatory responses—potentially by the JAK-STAT signaling pathway. Conclusions These findings suggest that rosuvastatin-induced disruption of microglial function may contribute to cognitive impairment. Our study elucidates potential pathways for this adverse effect and provides novel insights for developing preventive and therapeutic strategies.