Pterostilbene enhances Osimertinib sensitivity in non-small cell lung cancer through FGFR4-dependent ferroptosis

Background Osimertinib is a third-generation EGFR tyrosine kinase inhibitor that has become a mainstay treatment for EGFR-mutant non-small cell lung cancer (NSCLC). However, acquired resistance develops in most patients and ultimately compromises durable clinical benefit. Therefore, effective combination strategies to enhance Osimertinib sensitivity and delay or overcome resistance remain an urgent unmet clinical need. Methods The antitumor effects of pterostilbene in combination with Osimertinib were evaluated in EGFR-mutant and osimertinib-resistant NSCLC cell lines using CCK-8, colony formation, EdU incorporation, wound healing, and Transwell invasion assays. In vivo efficacy and safety were evaluated in nude mouse xenograft models. To investigate the underlying mechanisms, ferroptosis-related biochemical parameters, protein expression profiles, and transcriptomic profiles were analyzed. The involvement of ferroptosis and FGFR4 signaling was further validated using the ferroptosis inhibitor ferrostatin-1 (Fer-1) and FGFR4 siRNA-mediated knockdown. Results Pterostilbene markedly potentiated the antitumor efficacy of Osimertinib in vitro and in vivo and restored drug responsiveness in Osimertinib-resistant NSCLC cells. Mechanistically, the combination induced ferroptosis, as indicated by enhanced lipid peroxidation, intracellular Fe 2+ accumulation, and reduced expression of key ferroptosis-protective proteins, including GPX4 and xCT. Consistently, pharmacological inhibition of ferroptosis attenuated the antitumor effects of the combination. Furthermore, combined treatment modulated FGFR4-associated ERK/AKT signaling and disrupted redox and iron homeostasis. FGFR4 depletion significantly attenuated ferroptosis induction and reduced the synergistic anticancer effects of the combination, whereas FGFR4 re-expression restored treatment responsiveness, supporting an FGFR4-dependent therapeutic response. Conclusion This study demonstrates that pterostilbene enhances the antitumor efficacy of Osimertinib through the induction of FGFR4-dependent ferroptosis, providing mechanistic insights and suggesting a potential therapeutic strategy to overcome EGFR-TKI resistance in NSCLC.