Repurposing Lenalidomide for Refractory Behcet's Disease: Systematic Review and Computational Pharmacology Insights for Rare Disease Therapy.

INTRODUCTION: Lenalidomide is an immunomodulatory drug. Its repurposing for refractory Behcet's Disease is a promising strategy. Behcet's Disease is a rare and complex autoinflammatory condition. Current treatment options are limited. This study explored the drug's therapeutic potential using clinical and computational analyses. METHODS: This study included a systematic review of clinical case reports. Computational methods included toxicological predictions, network pharmacology to screen common targets of lenalidomide and Behcet's Disease, and the construction of protein-protein interaction networks utilizing tools such as ProTox-3.0, ADMETlab 3.0, and Cytoscape. Additionally, molecular docking (AutoDock Vina) and molecular dynamics simulations (GROMACS) were used to assess binding and stability. RESULTS: Clinical data showed low-dose lenalidomide provided rapid symptom relief and appeared to be well tolerated. Computational toxicology revealed a complex, dose-dependent safety profile. Network analysis identified 63 common targets. Seven core genes were found, including IL6, TNF, and JAK1. These genes were enriched in immune pathways, particularly the JAK-STAT cascade. Molecular docking and dynamics confirmed stable binding to key targets like IL6 and JAK1. DISCUSSION: Lenalidomide appears potentially effective in Behcet's Disease. Its action likely involves multi-target regulation of core immune pathways. Multi-target regulation of the JAKSTAT and TNF signaling cascades directly addresses the core autoinflammatory pathology of Behcet's Disease. The concordance between clinical efficacy and computational findings highlights its repurposing potential. The findings also stress the importance of dose optimization for safety, generating a promising low-dose safety hypothesis. CONCLUSION: Lenalidomide is a viable repurposing candidate warranting further clinical investigation for refractory Behcet's Disease. This strategy provides a mechanistically supported treatment for this rare disease. Combining network pharmacology and molecular dynamics provides a robust preclinical rationale for repurposing lenalidomide in Behcet's Disease.