Unveiling the potential mechanisms of gefitinib-induced neurotoxicity: A network toxicology approach.

Gefitinib, a first-line EGFR-TKI for NSCLC, frequently causes neurotoxic side effects, yet its underlying molecular mechanism remains poorly defined. This study adopted integrated network toxicology and molecular docking to uncover key targets and pathways driving gefitinib-induced neuronal damage. Gefitinib-targeted and neurotoxicity-related genes were intersected to identify 26 shared hub genes, including EGFR, MAPK3, MAPK14, ERBB2, and CASP3. KEGG enrichment analysis indicated that the MAPK signaling pathway dominated toxic processes, and molecular docking verified stable, high-affinity binding between gefitinib and these five core proteins (binding energy: -8.0 to -6.4 kcal/mol). Collectively, gefitinib suppresses neuronal EGFR, hyperactivates MAPK cascades and triggers CASP3-dependent apoptosis, which constitutes the core mechanism of its neurotoxicity. This work provides predictive molecular evidence for subsequent experimental validation and safer clinical use of gefitinib.