SIRT3-mediated deacetylation of FoxM1 prevents pulmonary fibrosis via modulating the activation of pulmonary fibroblasts.

Abstract

Idiopathic pulmonary fibrosis (IPF) is a life-threatening interstitial lung disease characterized by the abnormal activation of pulmonary fibroblasts. In our study, we demonstrated that FoxM1 is highly expressed in activated pulmonary fibroblasts, and its nuclear translocation plays a crucial role in conferring resistance to FasL-induced apoptosis in pulmonary fibroblasts. Disruption of FoxM1 function was shown to restore the ability to resolve fibrosis in mice treated with bleomycin. Mechanistic investigations revealed that a decrease in SIRT3 expression leads to increased acetylation of FoxM1, which is essential for the activation of pulmonary fibroblasts in vitro. Further, downregulation of SIRT3 expression enhances the stability of FoxM1, thereby accelerating bleomycin-induced pulmonary fibrosis through the activation of pulmonary fibroblasts. Importantly, treatment with nicotinamide riboside was found to suppress the activation of pulmonary fibroblasts and protect mice from bleomycin-induced pulmonary fibrosis by activating SIRT3. In summary, our findings highlight a critical role of the SIRT3/FoxM1 axis in regulating the activation of pulmonary fibroblasts. These insights suggest potential therapeutic strategies against pulmonary fibrosis, focusing on modulating this pathway for effective treatment. This work opens new avenues for the development of targeted therapies aimed at mitigating the progression of IPF.