CDDO-Me Overcomes Gefitinib Resistance in NSCLC by Targeting the Src/STAT3 Axis to Induce Apoptosis and Pyroptosis

Patients with EGFR-mutant non-small-cell lung cancer (NSCLC) develop acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), limiting the durability of targeted therapy. Bardoxolone methyl (CDDO-Me) has been reported to exert anti-inflammatory and anti-cancer activities. However, its role in acquired EGFR-TKI resistance remains unclear. Here, we found that CDDO-Me significantly enhanced sensitivity of resistant NSCLC cells to gefitinib, with combination index analysis confirming a synergistic interaction between CDDO-Me and gefitinib. Mechanistically, CDDO-Me induced mitochondrial dysfunction and reactive oxygen species (ROS) accumulation, thereby activating Caspase-3 mediated apoptosis and GSDME-dependent pyroptosis, as evidenced by increased lactate dehydrogenase (LDH) release. Network pharmacology and molecular docking analyses identified Src as a potential target of CDDO-Me. Cellular thermal shift assay (CETSA) confirmed cellular engagement between CDDO-Me and Src, and Western blot analysis showed that CDDO-Me suppressed Src/STAT3 signaling. Consistently, Src knockdown reduced the inhibitory effect of combined CDDO-Me and gefitinib treatment on colony formation and attenuated changes in apoptosis and pyroptosis regulatory proteins induced by the combination treatment. Collectively, these findings suggest that CDDO-Me enhances gefitinib sensitivity by targeting Src and suppressing Src/STAT3 signaling, leading to apoptosis and pyroptosis in gefitinib-resistant NSCLC cells. This study provides mechanistic evidence for further investigation of CDDO-Me-based combination strategies for gefitinib-resistant NSCLC.