Epigenetic-mediated positive feedback loop facilitates the progression of lung adenocarcinoma

Lung adenocarcinoma (LUAD) remains a leading cause of cancer-related mortality. We performed multi-omics approaches on LUAD samples spanning different stages, establishing a detailed epigenetic landscape. We identified 1,416 regions characterized by hypo-DNA methylation and hyperchromatin accessibility associated with high mortality and recurrence rates, serving as a biomarker panel for LUAD staging and diagnosis (AUC of 0.89 and 0.87 for two-class and multi-class models). Epigenetics-related transcription factors, especially the AP-1 family, were observed at these loci, and transcriptomic profiling indicated persistent activation of the mitogen-activated protein kinase (MAPK) signaling pathway. Hypomethylation and hyperaccessibility of AP-1 binding sites enhance EGFR and FGFBP1 expression, activating the MAPK pathway. This reveals an epigenetic-mediated positive feedback loop, MAPK→AP-1/Epigenetic Modifications→EGFR/FGFBP1→MAPK, in LUAD, highlighting the complex interplay between epigenetic modifications and LUAD progression, offering potential detection and treatment targets. These findings define a high-resolution, multi-stage epigenetic landscape of LUAD, providing a resource for biomarker discovery and mechanistic insight.