Abstract Body: Breakdown of the lung microvascular endothelial barrier is a defining event in acute lung injury (ALI), yet the molecular pathways that destabilize endothelial junctions remain incompletely understood. Building on our recent work, we have developed a mechanistic model positioning class IIa histone deacetylase HDAC7 as a critical cytoplasmic regulator of junctional remodeling during inflammatory stress. In human lung microvascular endothelial cells, edemagenic stimulation with lipopolysaccharide (LPS) selectively induces HDAC7, distinct from other class IIa HDACs, like HDACs 4 and 5, and promotes its phosphorylation-dependent export from the nucleus. Once in the cytoplasm, HDAC7 engages protein phosphatase 2A (PP2A) and junctional proteins desmoplakin (DSP) and plakoglobin (JUP), forming a signaling hub that influences endothelial cell-cell adhesion. Our integrated analysis suggests that phosphorylated HDAC7 may limit PP2A activity toward key junctional substrates, thereby enhancing DSP and β-catenin phosphorylation and weakening endothelial junctions. Conversely, PP2A activation, particularly through hepatocyte growth factor (HGF) and its GAB1/SHP2 signaling axis, appears to promote HDAC7 dephosphorylation and nuclear re-entry, relieving its inhibitory influence on junctional complexes. This framework provides a unifying explanation for the opposing effects of LPS and HGF on endothelial barrier function and highlights HDAC7 phosphorylation status as a potential molecular switch governing PP2A-mediated junctional stability. Together, these findings support a model in which HDAC7-PP2A crosstalk orchestrates dynamic endothelial junctional remodeling during ALI. Defining how this signaling axis controls DSP/JUP organization and barrier integrity may reveal new therapeutic strategies aimed at restoring lung vascular function in inflammatory injury.