Single-cell and spatial transcriptomic colocalization analysis reveals the roles of histone deacetylation in lung...

Lung adenocarcinoma (LUAD), as the most prevalent pathological subtype of lung cancer, is characterized by heterogeneity and therapy resistance that limit clinical efficacy. Histone deacetylation is a key epigenetic mechanism involved in tumorigenesis; however, its spatial distribution and regulatory network in LUAD remain poorly understood.

We integrated scRNA-seq, spatial transcriptomics, and molecular biology to investigate histone deacetylase-related genes (HDRGs) in LUAD. Using datasets (GSE131907, GSE189487, TCGA-LUAD), we analyzed HDRG activity, built a 7-gene prognostic model, and validated the FOXA1-HDAC2 axis experimentally.

scRNA-seq identified 9 cell types in LUAD microenvironment, with malignant epithelial cells showing high HDRG activity. Spatial analysis revealed HDAC2 and BRD2 co-enrichment in tumor cores, correlated with pyrimidine metabolism. The 7-gene signature demonstrated robust prognostic value across cohorts. High HDAC2 expression correlated with poor prognosis, immune remodeling, and therapy resistance. FOXA1 bound the HDAC2 promoter to enhance its expression; disrupting this axis suppressed tumor progression. HDAC2 knockdown synergized with ERK inhibitor SCH772984 to inhibit tumor growth.

This study elucidates the pivotal role of HDRGs in LUAD heterogeneity and malignant progression. The FOXA1-HDAC2 axis is identified as a novel regulatory pathway, providing a theoretical and experimental foundation for prognostic stratification and combination targeted therapy in LUAD.