HOXA5 Suppresses NEK7‐Mediated Alveolar Epithelial Pyroptosis in Acute Lung Injury by Transcriptionally Inhibiting KAT2A

ABSTRACT Alveolar epithelial cell pyroptosis exacerbates inflammation and tissue damage by releasing inflammatory mediators, thereby promoting the development of acute lung injury (ALI). However, the fundamental mechanism underlying alveolar epithelial cell pyroptosis in ALI has not yet been elucidated. Lipopolysaccharide (LPS) was used to simulate ALI in vitro and in vivo. Cell viability was measured using the MTT assay. The expression of these molecules was determined by Western blot, enzyme‐linked immunosorbent assay (ELISA), quantitative real‐time polymerase chain reaction (RT‐qPCR), immunofluorescence, and immunohistochemical assays. The level of pyroptosis was determined using flow cytometry. The interactions between the molecules were validated using co‐immunoprecipitation, chromatin immunoprecipitation, and luciferase reporter assays. Homeobox A5 (HOXA5) was expressed at low levels, whereas lysine acetyltransferase 2A (KAT2A) and NIMA‐related kinase 7 (NEK7) were highly expressed in LPS‐induced (type II alveolar epithelial) ATII cells and mice. HOXA5 overexpression suppressed pyroptosis in LPS‐induced ATII cells and mice. Notably, KAT2A overexpression abolished the effects induced by HOXA5 overexpression in LPS‐induced ATII cells. Mechanistically, HOXA5 inhibits KAT2A transcriptional activity by binding to the KAT2A promoter. KAT2A positively regulates NEK7 by promoting H3K9ac/H3K27ac enrichment in the NEK7 promoter. In conclusion, HOXA5 indirectly inhibits NEK7 expression by inhibiting KAT2A transcriptional activity, thereby suppressing pyroptosis in alveolar epithelial cells in ALI.