Loss of DDX24 inhibits lung cancer progression by stimulating IKBKG splicing-mediated autophagy
Lung cancer remains a major global health burden with limited therapeutic options. Alternative splicing, a critical post-transcriptional process, contributes to lung cancer progression through autophagy, although the underlying mechanisms remain largely unexplored. Here we reveal that loss of DDX24, an RNA-binding protein, suppresses lung cancer growth by promoting autophagy. Mechanistically, DDX24 regulates the alternative splicing of autophagy-related genes, including IKBKG. We demonstrate that DDX24 directly binds to IKBKG pre-mRNA, whereas DDX24 ablation promotes the generation of a pro-autophagic long splicing variant. Functional rescue experiments confirm that the long IKBKG isoform-mediated autophagy confers the anti-tumor effects of DDX24 depletion. These findings uncover a novel regulatory axis involving DDX24, IKBKG splicing, and autophagy in lung cancer and provide a potential therapeutic target for this devastating disease. Overall design: Comparative gene expression profiling analysis of RNA-seq data for A549 cells with DDX24 knockdown or not