Tuberostemonine may enhance the function of the SLC7A11/glutamate antiporter to restrain the ferroptosis to alleviate pulmonary fibrosis

Stemona is a medicinal plant that has been used in China for thousands of years to treat respiratory diseases such as cough and tuberculosis. The tuberostemonine is the component of the Stemona tuberosa Lour., Stemona sessilifolia (Miq.) Miq. or Stemona japonica (Blume) Miq. (The plant name has been checked with http://www.theplantlist.org), of which multiple biological activities has been verified. However, whether it may alleviate pulmonary fibrosis via regulating ferroptosis mechanism has not been confirmed. The aim of this study is to observe whether tuberostemonine alleviates pulmonary fibrosis by enhancing the function of the SLC7A11/glutamate antiporter to restrain the ferroptosis. We validated the effects of tuberostemonine and ferroptosis on TGF-β1-induced proliferation of human lung fibroblast and bleomycin-induced pulmonary fibrosis in mice. In vitro, the ferroptosis effect of TGF-β1 on human lung fibroblast were examined and the activity of ɑ-SMA, collagen, hydroxyproline and ferrous ions in cells were also examined. In vivo, ferroptosis impacts respiratory function. Inflammatory manifestations, hydroxyproline, collagen activity and ferrous ions in the lung or blood were subject to evaluation. Tuberostemonine significantly improved respiratory function in mice with bleomycin-induced pulmonary fibrosis, decreased cellular and lung hydroxyproline content, reduced inflammation and collagen deposition in cells and lung, and promoted an increase in the SLC7A11 and GPX4 proteins. Tuberostemonine inhibits the ferroptosis phenomenon, up-regulates SLC7A11, GPX4 and GSH, and down-regulates the accumulation of iron and ROS. Tuberostemonine significantly inhibited ferroptosis and improved pulmonary fibrosis both in vivo and vitro.