Microglia as a key mediator in rosuvastatin-associated cognitive impairment

  • Neurotoxicology. 2026 Mar:113:103405. doi: 10.1016/j.neuro.2026.103405.
Xianzheng Sang  1 ,  Yichao Ye  2 ,  Chengzi Yang  3 ,  Xiaoxiang Hou  4 ,  Yangu Guo  5 ,  Hantong Shi  6 ,  Chunhui Wang  7 ,  Wen Chen  8 ,  Danfeng Zhang  9 ,  Lijun Hou  10
Affiliations
  • 1. Department of Neurosurgery, The Second Affiliated Hospital of Navy Medical University, Shanghai 200003, China. Electronic address: [email protected].
  • 2. Department of Neurosurgery, The Second Affiliated Hospital of Navy Medical University, Shanghai 200003, China. Electronic address: [email protected].
  • 3. Department of Neurosurgery, The Second Affiliated Hospital of Navy Medical University, Shanghai 200003, China. Electronic address: [email protected].
  • 4. Department of Neurosurgery, The Second Affiliated Hospital of Navy Medical University, Shanghai 200003, China. Electronic address: [email protected].
  • 5. Department of Neurosurgery, The Second Affiliated Hospital of Navy Medical University, Shanghai 200003, China. Electronic address: [email protected].
  • 6. Department of Neurosurgery, The Second Affiliated Hospital of Navy Medical University, Shanghai 200003, China. Electronic address: [email protected].
  • 7. Department of Neurosurgery, No. 905 Hospital of the People's Liberation Army Navy, Shanghai 200052, China. Electronic address: [email protected].
  • 8. Department of Neurosurgery, The Second Affiliated Hospital of Navy Medical University, Shanghai 200003, China. Electronic address: [email protected].
  • 9. Department of Neurosurgery, The Second Affiliated Hospital of Navy Medical University, Shanghai 200003, China. Electronic address: [email protected].
  • 10. Department of Neurosurgery, The Second Affiliated Hospital of Navy Medical University, Shanghai 200003, China. Electronic address: [email protected].
PMID: 41690424 DOI: 10.1016/j.neuro.2026.103405
Abstract

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.

Keywords
Cognitive impairment; Computational simulations; Hydroxymethylglutaryl-coenzyme A reductase inhibitors; Mendelian randomization analysis; Microglia; Network toxicology.
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