BACKGROUND: Sepsis, characterized by a severe systemic inflammatory response leading to organ failure, often results in acute respiratory dysfunction in approximately half of affected individuals. Understanding the molecular mechanisms underlying pulmonary impairment in sepsis is critical for advancing clinical interventions. This study aimed to investigate the role and mechanism of histone deacetylase 2 (HDAC2) in the progression of septic lung injury (SLI). METHODS: To establish the SLI model, cecal ligation and puncture (CLP) was performed in vivo. Hematoxylin-eosin (HE) staining was used to assess pathological changes in lung tissue. For in vitro experiments, lipopolysaccharide (LPS)-induced macrophages were employed to model SLI. Macrophage activation was evaluated by analyzing the expression levels of F4/80, inducible nitric oxide synthase (iNOS), and CD86. Protein-protein interactions were analyzed via co-immunoprecipitation (CO-IP), while transcriptional regulation was examined using luciferase assays and chromatin immunoprecipitation (ChIP). RESULTS: The findings demonstrated that HDAC2 knockdown mitigates SLI severity and suppresses macrophage activation. Mechanistically, HDAC2 directly interacts with SOX2 to inhibit its acetylation and destabilize the protein. Furthermore, SOX2 binds to the STAMP2 promoter region and modulates its transcriptional activity. CONCLUSION: Collectively, the HDAC2/SOX2/STAMP2 signaling axis represents a potential therapeutic target for the treatment of septic lung injury.