Objective Phosphatidylinositol 3-kinase gamma (PI3Kγ) plays a critical role in the immune system, thus identifying PI3Kγ as a potential therapeutic target for inflammation. However, there are few reports of selective PI3Kγ inhibitors being used in the field of anti-inflammation thus far, therefore, great efforts would be needed to study the anti-inflammatory effect of PI3Kγ inhibitors. In the present study, Eganelisib, the PI3Kγ inhibitor in clinical studies, was chosen to investigate the anti-inflammation and PI3Kγ inhibitory preference.Methods Firstly, lipopolysaccharide (LPS)-induced RAW264.7 macrophage was used as in vitro inflammation model to estimate the anti-inflammation of Eganelisib. Then, a modeling strategy integrated common feature pharmacophore, receptor-ligand pharmacophore, and molecular dynamics simulation was employed to reveal the γ-selective mechanism of Eganelisib.Results Eganelisib treatment could downregulate the production of inflammatory mediators by suppressing the PI3K signaling pathway. The common feature and receptor-ligand pharmacophore models found that the hydrogen bond and hydrophobic features play key roles in the interaction between Eganelisib and PI3Kγ protein. Several key residues such as Val882, Met804, Trp812, and Ile963 contributing to favorable PI3Kγ binding were highlighted in molecular dynamics simulation.Conclusion Our findings provide the initial anti-inflammatory effect of Eganelisib, and reveal the mechanism of selective binding between inhibitors and PI3Kγ, which may provide some guidelines for the development of anti-inflammatory PI3Kγ inhibitors.