Angiogenesis is a hallmark of lung adenocarcinoma (LUAD) and a leading cause of mortality. Identifying potential therapeutic targets that modulate this process is of critical clinical importance. Here, we established a 12-gene risk-scoring model through bioinformatics screening and systematically delineated the molecular function of H2AC19, a previously poorly understood histone variant within this signature. Analysis of human LUAD specimens revealed elevated H2AC19 expression, which correlated positively with angiogenesis markers and advanced clinical stage and negatively with patient prognosis. Functional validation using CRISPR/Cas9 in patient-derived organoids (PDOs), in vitro cell models and in vivo xenografts demonstrated that H2AC19 promotes angiogenesis and tumor growth. Mechanistically, H2AC19 recruits p300 through its amino acid residues 24-88 to specifically augment H3K27 acetylation at the EGR1 promoter region, thereby triggering EGR1 transcriptional activation and subsequently promoting MMP-1-driven angiogenesis and progression of LUAD. Furthermore, we evaluated the therapeutic potential of lipid nanoparticles (LNP)-encapsulated siRNA targeting H2AC19, which significantly suppressed angiogenesis and LUAD progression. Collectively, our findings establish a critical role for H2AC19 in governing angiogenesis and highlight its potential as a promising therapeutic target for LUAD.

Lung adenocarcinoma  /  Angiogenesis  /  H2AC19  /  Epigenetic regulation  /  Therapeutic target  /  EGR1  /  MMP-1  /  P300