Macrophage KAT8 Protects Against LPS-induced Acute Lung Injury by SP1 Acetylation

Acute lung injury (ALI) is a severe clinical condition with high mortality and limited therapeutic options. Macrophages play a central role in the inflammatory response during ALI, yet the underlying regulatory mechanisms remain incompletely understood. In this study, we identify lysine acetyltransferase 8 (KAT8) as a critical protective regulator in LPS-induced ALI. We demonstrate that KAT8 expression is downregulated in lung macrophages following LPS challenge. Genetic deletion or pharmacological inhibition of KAT8 exacerbate lung inflammation and injury during ALI. Mechanistically, KAT8 directly interacts with and acetylates the transcription factor specificity protein 1 (SP1), leading to suppression of NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome and the expression of pro-inflammatory cytokines. These findings reveal that KAT8/SP1 axis represents a novel pathway in the regulation of lung inflammation, offering new insights into the post-translational control of ALI pathogenesis.