Atorvastatin ameliorates chronic subdural hematomas by interrupting the 'chronic subdural hematoma cycle' via inhibition of the inflammatory response

Chronic subdural hematomas (CSDHs) are prevalent neurosurgical occurrences characterized by progressive hemorrhagic expansion, which is primarily mediated by persistent inflammation, angiogenesis and fibrinolytic dysregulation. Atorvastatin, a widely used lipid-lowering agent with known anti-inflammatory and angiogenesis-modulating properties, has shown therapeutic potential in CSDH management. In the present study, network pharmacology and experimental validation were combined to elucidate the underlying mechanisms of atorvastatin in CSDH treatment. Potential targets were identified through database mining and Venn analysis, followed by Gene Ontology/Kyoto Encyclopedia of Genes and Genomes enrichment, protein-protein interaction network construction and molecular docking. In vitro experiments were performed to evaluate the effects of atorvastatin on a tumor necrosis factor-α-induced endothelial inflammation model, including on inflammatory cytokine secretion, target gene expression, endothelial permeability and tube formation. A total of 19 candidate therapeutic targets were identified, which were predominantly involved in the inflammatory response, coagulation, fibrinolysis and angiogenesis pathways. Core targets, including matrix metalloproteinase (MMP)-2, MMP-9, interleukin (IL)-6, C-X-C motif chemokine ligand 8/IL-8 and Serpin family E member 1, demonstrated strong binding affinities with atorvastatin via molecular docking analyses. Furthermore, functional experiments revealed that atorvastatin significantly suppressed the expression of pro-inflammatory cytokines and adhesion molecules, mitigated endothelial barrier dysfunction, reversed the inhibitory effect of inflammation on endothelial tube formation and downregulated key pathogenic genes. Collectively, these findings suggest that atorvastatin may disrupt the 'CSDH cycle' by modulating critical inflammatory, angiogenic and fibrinolytic mechanisms, providing a scientific rationale for its therapeutic application in CSDH management. Further in vivo studies are warranted to validate these preliminary observations and to explore clinical translation to the clinic.

atorvastatin; chronic subdural hematoma; chronic subdural hematoma cycle; inflammatory response.