{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T16:03:42Z","timestamp":1784649822907,"version":"3.55.0"},"reference-count":42,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T00:00:00Z","timestamp":1784592000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Shanghai Magnolia Talent Plan Pujiang Project","award":["24PJD042"],"award-info":[{"award-number":["24PJD042"]}]},{"name":"SciTech Funding via CSPFTZ Lin-gang Special Area Marine Biomedical Innovation Platform","award":["RWS2024003"],"award-info":[{"award-number":["RWS2024003"]}]},{"name":"Shanghai Frontiers Research Center of the Hadal Biosphere and Natural Science Foundation of Shanghai","award":["21ZR1427300"],"award-info":[{"award-number":["21ZR1427300"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/ijms27146481","type":"journal-article","created":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T15:17:52Z","timestamp":1784647072000},"page":"6481","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["CDDO-Me Overcomes Gefitinib Resistance in NSCLC by Targeting the Src\/STAT3 Axis to Induce Apoptosis and Pyroptosis"],"prefix":"10.3390","volume":"27","author":[{"given":"Tongtong","family":"Li","sequence":"first","affiliation":[{"name":"International Research Centre for Food and Health, College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China"},{"name":"Department of Chemistry, College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiyu","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Chemistry, College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruoxian","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Chemistry, College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xudong","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Chemistry, College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Chemistry, College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjuan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Chemistry, College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiahui","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Chemistry, College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Chemistry, College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongtong","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Chemistry, College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7009-9187","authenticated-orcid":false,"given":"Ning","family":"Liu","sequence":"additional","affiliation":[{"name":"International Research Centre for Food and Health, College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China"},{"name":"Department of Chemistry, College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China"},{"name":"Marine Biomedical Science and Technology Innovation Platform of Lin-Gang Special Area, Shanghai 201306, China"},{"name":"Shanghai Engineering Research Center of Aquatic-Product Processing & Preservation, Shanghai 201306, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/S0140-6736(21)00312-3","article-title":"Lung Cancer","volume":"398","author":"Thai","year":"2021","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1056\/NEJMoa1913662","article-title":"Overall Survival with Osimertinib in Untreated, EGFR-Mutated Advanced NSCLC","volume":"382","author":"Ramalingam","year":"2020","journal-title":"N. 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