Genistein inhibits lung adenocarcinoma cell proliferation by targeting KAT8/H3K27la to modulate histone lactylation: effects and mechanisms

Abstract: Human lung adenocarcinoma is a common malignant tumor of the respiratory system, whose proliferative characteristics pose significant therapeutic challenges. This study aims to investigate the inhibitory effect of Genistin (GEN) on it and the underlying molecular mechanisms. Various experimental methods were employed, including the CCK-8 assay, colony formation assay, wound healing assay, flow cytometry, RNA sequencing, metabolomic analysis, and Western blot. The results showed that Genistin significantly inhibited the growth of lung adenocarcinoma PC-9 and H1299 cells in a dose-dependent manner. Concurrently, it arrested the cell cycle at the G1 phase by downregulating the expression of CDK2. RNA sequencing analysis indicated that genes related to cellular glycolytic metabolism were significantly enriched in the Genistin-treated group. Further metabolomic analysis revealed that the differentially abundant metabolites were notably enriched in the glycolysis pathway. Moreover, lactate, as a primary metabolic product, was markedly decreased in the Genistin-treated group. Co-immunoprecipitation (Co-IP) experiments further demonstrated that Genistin selectively reduces the lactylation level at the histone H3K27 site by affecting the interaction between KAT8 and H3K27. Animal studies indicated that Genistin can inhibit the in vivo growth of human lung adenocarcinoma cells. In summary, Genistin significantly suppresses the proliferation of human lung adenocarcinoma cells by targeting the KAT8/H3K27la axis through multiple mechanistic pathways. This suggests its potential as a novel anti-lung cancer agent, and future research should further explore its value in clinical therapeutic applications.