Objective To investigate the effects of GCN5-mediated histone H3 acetylation (ac) on the proliferation, apoptosis and inflammatory factors of lipopolysaccharide (LPS) -induced alveolar epithelial cells. Methods A549 cells were randomly divided into 6 groups: control group, LPS group, NC+LPS group, GCN5+LPS group, MB-3 (GCN5 inhibitor) +LPS group and GCN5+MB-3+LPS group. Expression levels of H3K9ac, H3K14ac, H3K23ac, GCN5, and cell viability, cell proliferation, apoptosis, levels of inflammatory factors were compared between different groups. Quantitative polymerase chain reaction (qPCR) was used to detect the GCN5 mRNA expression; CCK-8 kit was used to detect cell viability; Cell proliferation was detected by EdU assay; apoptosis was detected by flow cytometry. The expression of GCN5, H3K9ac, H3K14ac, H3K23ac, Caspase-3 and Bcl-2 proteins were detected by Western blotting. The levels of inflammatory factors [interleukin (IL) -1β, IL-6 and tumor necrosis factor (TNF) -α] were determined by enzyme-linked immunosorbent assay (ELISA). Results Compared with control group, the levels of H3K9ac, H3K14ac and H3K23ac were decreased, the mRNA and protein expression of GCN5 were down-regulated, and the cell viability and proliferation were decreased, cell apoptosis was increased, Caspase-3 protein expression was up-regulated while Bcl-2 was down-regulated, the levels of inflammatory factors were increased in LPS group (P<0.05). Compared with the LPS group, no significant changes existed in the levels of the mRNA and protein expression of GCN5 in NC+LPS group (P>0.05), the mRNA and protein expression of GCN5 were up-regulated, the levels of H3K9ac, H3K14ac and H3K23ac were increased, and the cell viability and proliferation were increased, cell apoptosis was decreased, Caspase-3 protein expression was down-regulated while Bcl-2 was up-regulated, the levels of IL-1β, IL-6 and TNF-α were decreased in GCN5+LPS group (P<0.05). Compared with GCN5+LPS group, the levels of H3K9ac, H3K14ac and H3K23ac were decreased, and the cell viability and proliferation were reduced, cell apoptosis was elevated, the levels of IL-1β, IL-6 and TNF-α were increased in GCN5+MB-3+LPS group (P<0.05). Conclusion GCN5 overexpression could resist LPS-induced injuries of alveolar epithelial cells such as abnormal proliferation and apoptosis and inflammatory factors production, which could be related to the increase of histone H3 acetylation level.