Background: Smoking-induced glycocalyx significantly contributes to the pathogenesis of chronic obstructive pulmonary disease (COPD). Forkhead box protein 1 (Foxp1) reduces the expression of matrix metalloproteinase 9 (MMP9), thereby preventing glycocalyx injury. Therefore, we hypothesized that Foxp1 may maintain the integrity of the glycocalyx by inhibiting MMP9, thereby alleviating COPD.

Methods: We established COPD mouse models and intervened with Adeno-associated virus 9 (AAV9)-Foxp1. The mean linear intercept (MLI) and apoptosis of the lung tissue were analyzed using histological staining. Human pulmonary microvascular endothelial cells (hPMVECs) were transfected with Foxp1 plasmid and or MMP9 plasmid and then exposed to cigarette smoke extract (CSE) to establish in vitro cellular model. The expressions of glycocalyx-related proteins (Versican, syndecan-1 and MMP9) and Foxp1 were assessed using Western blotting and quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis. Cellular viability, apoptosis, endothelial permeability, and tube formation capabilities were determined using the cell counting kit-8 (CCK-8) assay, flow cytometry, transwell assay, and tube formation assay, respectively.

Results: In vivo, AAV9-Foxp1 treatment significantly reduced MLI and endothelial apoptosis in COPD mice (p < 0.05). It also suppressed MMP9 expression while increasing Versican and syndecan-1 levels, indicating glycocalyx protection (p < 0.05). In vitro, Foxp1 overexpression counteracted CSE-induced damage by enhancing cell viability, reducing apoptosis, improving endothelial barrier function, and promoting tube formation (p < 0.05). Furthermore, Foxp1 upregulation restored glycocalyx integrity by increasing syndecan-1 and decreasing MMP9 expression. However, these protective effects were abolished when MMP9 was overexpressed simultaneously, confirming that Foxp1 acts through the inhibition of MMP9 (p < 0.05).

Conclusion: Foxp1 protects glycocalyx from injury to relieve COPD by downregulating MMP9, highlighting its potential as a promising therapeutic target.