FSTL1 Promotes Alveolar epithelial cells Aging and Worsens Pulmonary Fibrosis by Affecting SENP1-Mediated DeSUMOylation

Abstract Background Alveolar epithelial cells (AECs) senescence-induced changes of lung mesenchymal cells are the key link to starting the progress of pulmonary fibrosis. Follistatin-like 1 (FSTL1) plays a central regulatory role in the complex process of senescence and pulmonary fibrosis by enhancing transforming growth factor beta 1 (TGFβ1) signal pathway activity. Activation of Smad4 and Ras rely on SENP1 (SUMO-specific peptidase 1)-mediated deSUMOylation during TGFβ signaling pathway activation. We hypothesized that SENP1-mediated deSUMOylation may be a potential therapeutic target by modulating FSTL1-regulated cellular senescence in pulmonary fibrosis. Methods Lung tissues of idiopathic pulmonary fibrosis (IPF) patients were used to observe the expression of FSTL1 in and SENP1 in AECs senescence. Lentivirus-packaged short hairpin RNA against SENP1 (LV-SENP1shRNA) was constructed to intervene in FSTL1-induced aging model both in vitro and in vivo. The phenomenon of FSTL1 promoting AECs senescence was evaluated and the mechanism of LV-SENP1shRNA affecting FSTL1 promoting pulmonary fibrosis was elucidated. Results FSTL1 expression was upregulated in the lung tissues of patients with IPF and that SENP1 was overexpressed in senescent AECs. TGFβ1-induced FSTL1 not only promoted AECs senescence, but also upregulated SENP1 expression. Interfering SENP1 expression inhibited FSTL1 promotion of AECs senescence and improved pulmonary fibrosis in mouse lungs. FSTL1 enhancement of TGFβ1 signaling pathway activation was dependent on SENP1 in AECs senescence. Conclusions Our work identified a novel mechanism by which FSTL1 is involved in AECs senescence. Inhibition of SENP1 in epithelial cells alleviated pulmonary fibrosis by blocking FSTL1-enhanced TGF signaling pathway.