Network pharmacology and molecular simulation suggest potential mechanisms of sorafenib-induced HFSR.

BACKGROUND

Hand-foot skin reaction (HFSR) is a dose-limiting adverse effect of sorafenib, yet its molecular etiology remains elusive.

OBJECTIVES

This study investigated the potential targets and pathways of sorafenib-induced HFSR using integrated computational methods.

METHODS

Network pharmacology was used to identify overlapping targets between sorafenib and HFSR. After pathway enrichment, hub targets were analyzed via molecular docking and 100-ns molecular dynamics (MD) simulations to assess binding stability.

RESULTS

Network analysis identified 71 targets, primarily in the MAPK/ERK and PI3K-Akt pathways. EGFR and MAPK1 (ERK2) were identified as key hubs. MD simulations revealed that sorafenib maintains superior structural stability when complexed with EGFR rather than with ERK2.

CONCLUSION

Computational evidence suggests that off-target engagement and RTK-MAPK/PI3K dysregulation mediate HFSR. These findings provide a mechanistic basis for mitigating sorafenib-induced toxicity, pending experimental validation.