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Although platinum\u2010based chemotherapies such as cisplatin are standard treatments for non\u2010small cell lung cancer (NSCLC), their efficacy is often hindered by the development of drug resistance. The present study aimed to investigate the therapeutic potential and molecular mechanisms of quercetin in monotherapy and in combination treatment with cisplatin in NSCLC. In\u00a0vitro and in\u00a0vivo models of cisplatin\u2010resistant NSCLC were employed to evaluate the therapeutic efficacy of quercetin\u2010cisplatin combination therapy. Comprehensive mechanistic investigations included lncRNA sequencing, Western blotting, immunofluorescence, malondialdehyde (MDA) quantification, reactive oxygen species (ROS) detection, microscale thermophoresis (MST), real\u2010time quantitative PCR, and dual\u2010luciferase reporter assays. This study examines the potential of combining quercetin with cisplatin to overcome chemoresistance in NSCLC models, focusing on the molecular pathways involved. We determined that ferroptosis is the primary cause of cell death induced by quercetin in NSCLC and associated animal models. As a master transcriptional factor, p53 orchestrates a diverse network of downstream effector genes. Research shows that constant expression of wild\u2010type p53 in cancer cells induces ferroptosis, which is caused by inhibiting the xCT\/GPX4 axis and managing iron homeostasis and lipid peroxidation pathways. We found that p53 knockdown inhibits quercetin's anticancer effects. Transcriptomics revealed significant alterations in the long non\u2010coding DDB2\u2010AS1, a new lncRNA sequence associated with damage\u2010specific DNA binding protein 2 (DDB2), after quercetin treatment of cisplatin\u2010resistant NSCLC. A further study showed that quercetin upregulates the expression of p53 by regulating the lncRNA DDB2\u2010AS1\/miR\u20104728\u20105p pathway, thereby inducing ferroptosis in cisplatin\u2010resistant NSCLC cells, thus overcoming cisplatin resistance. These findings demonstrate that quercetin induces ferroptosis through the DDB2\u2010AS1\/miR\u20104728\u20105p\/p53 axis, thereby reversing cisplatin resistance in NSCLC, and highlighting its potential as an effective adjuvant in NSCLC chemotherapy.<\/jats:p>","DOI":"10.1002\/ptr.70216","type":"journal-article","created":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T11:35:38Z","timestamp":1768995338000},"page":"1230-1251","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Quercetin Overcomes Cisplatin Resistance by Inducing Ferroptosis via the\n                    <scp>DDB2<\/scp>\n                    \u2010\n                    <scp>AS1<\/scp>\n                    \/\n                    <scp>miR<\/scp>\n                    \u20104728\u20105p\/p53 Axis"],"prefix":"10.1002","volume":"40","author":[{"given":"Meng","family":"Li","sequence":"first","affiliation":[{"name":"School of Pharmacy, Zhejiang Provincial Key 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Zhejiang Province Hangzhou Normal University  Zhejiang Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xia","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Zhejiang Provincial Key Laboratory of Anti\u2010Cancer Chinese Medicines and Natural Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province Hangzhou Normal University  Zhejiang Hangzhou China"},{"name":"Liangzhu Laboratory Zhejiang University  Zhejiang Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi\u2010ran","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Zhejiang Provincial Key Laboratory of Anti\u2010Cancer Chinese Medicines and Natural Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center 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