Quercetin Overcomes Cisplatin Resistance by Inducing Ferroptosis via the DDB2 ‐ AS1 / miR ‐4728‐5p/p53 Axis

Lung cancers are among the most widespread and deadly cancers worldwide. Although platinum-based chemotherapies such as cisplatin are standard treatments for non-small 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 vitro and in vivo models of cisplatin-resistant NSCLC were employed to evaluate the therapeutic efficacy of quercetin-cisplatin combination therapy. Comprehensive mechanistic investigations included lncRNA sequencing, Western blotting, immunofluorescence, malondialdehyde (MDA) quantification, reactive oxygen species (ROS) detection, microscale thermophoresis (MST), real-time quantitative PCR, and dual-luciferase 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-type 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-coding DDB2-AS1, a new lncRNA sequence associated with damage-specific DNA binding protein 2 (DDB2), after quercetin treatment of cisplatin-resistant NSCLC. A further study showed that quercetin upregulates the expression of p53 by regulating the lncRNA DDB2-AS1/miR-4728-5p pathway, thereby inducing ferroptosis in cisplatin-resistant NSCLC cells, thus overcoming cisplatin resistance. These findings demonstrate that quercetin induces ferroptosis through the DDB2-AS1/miR-4728-5p/p53 axis, thereby reversing cisplatin resistance in NSCLC, and highlighting its potential as an effective adjuvant in NSCLC chemotherapy.