Inhibition of DLX6 sensitizes lung adenocarcinoma to cisplatin via GPX4-dependent ferroptosis.
BACKGROUND Lung adenocarcinoma (LUAD) is a leading cause of cancer-related mortality worldwide, with limited treatment options due to inherent chemotherapy resistance. Ferroptosis, an iron-dependent form of regulated cell death, has recently emerged as a promising strategy to overcome this resistance. Inducing ferroptosis may sensitize LUAD cells to chemotherapy, but its molecular regulators and therapeutic potential remain largely unexplored. This study aims to investigate the role of Distal-less homeobox 6 (DLX6) in regulating ferroptosis and its contribution to LUAD progression. METHODS To elucidate the function of DLX6 in LUAD, we employed a multi-omics approach, integrating TCGA data analysis, in vitro cell culture models, and in vivo xenograft experiments. Transcriptome sequencing, chromatin immunoprecipitation (ChIP) assays, and dual-luciferase reporter assays were utilized to uncover the underlying molecular mechanisms. RESULTS We found that DLX6 is significantly upregulated in LUAD and associated with poor patient prognosis. Functional studies showed that silencing DLX6 suppressed cell proliferation, triggered ferroptosis, and sensitized LUAD cells to chemotherapy. Mechanistically, DLX6 acted as a transcriptional activator of Glutathione Peroxidase 4 (GPX4), a central regulator of ferroptosis, by directly binding to its promoter region. Inhibition of DLX6 triggered ferroptosis in LUAD cells, enhancing treatment sensitivity to cisplatin. CONCLUSIONS Our findings highlight DLX6 as a key regulator of ferroptosis and cisplatin sensitivity in LUAD. By promoting GPX4 expression and inhibiting ferroptosis, DLX6 plays a crucial role in LUAD progression. This study provides valuable insights into the molecular mechanisms driving LUAD and offers a potential therapeutic target for sensitizing cisplatin treatment and improving chemotherapy resistance.