α-Hederin promotes ferroptosis and reverses cisplatin chemoresistance in non-small cell lung cancer

Background: Cisplatin is a core chemotherapy regimen in non-small cell lung cancer (NSCLC). However, chemoresistance to cisplatin leads to a poor prognosis in NSCLC. alpha-Hederin is a natural compound extracted from Nigella sativa. The study aims to explore the effects of alpha-Hederin on cisplatin resistance in NSCLC. Methods: NSCLC cisplatin-resistant cell lines A549/DPP and PC-9 were cultured to evaluate the efficacy of alpha-Hederin in the treatment of NSCLC in vitro and in vivo. Metabolomics and RNA-seq analysis were used to determine the potential mechanisms of action of alpha-Hederin. Results: The results showed that alpha-Hederin inhibited cisplatin-resistant NSCLC cells proliferation and metastasis. Mice xenograft, orthotopic, and metastatic A549/DPP cell models also showed the anti-tumor effects of alpha-Hederin. The metabolomics and RNA-seq analysis results showed that alpha-Hederin activated DDIT3/ATF3 pathway and ferroptosis via silencing SLC7A11 and GPX4. Furthermore, alpha-Hederin enhanced the nuclear expression of EGR1. Bioinformatics and luciferase experiments confirmed that EGR1 binds to the miR96-5p promoter region, inhibiting transcription. In addition, miR-96-5p directly suppressed the levels of DDIT3. Conclusion: This study revealed that alpha-Hederin activated EGR1 nuclear translocation and directly repressed miR-96-5p. It also promoted DDIT3/ATF3-mediated ferroptosis and reversed cisplatin resistance in NSCLC.