FSP1 Acts in Parallel with GPX4 to Inhibit Ferroptosis in Chronic Obstructive Pulmonary Disease.

GPX4 (glutathione peroxidase 4) has recently been reported to play an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). FSP1 (ferroptosis suppressor protein-1) is a protein that defends against ferroptosis in parallel with GPX4, but its role in the pathogenesis of COPD remains unexplored, and further research is needed. Normal and COPD lung tissues were obtained from lobectomy and lung transplant specimens, respectively. FSP1-overexpressing mice were established by monthly transfection with adenoassociated virus 9-FSP1 through modified intranasal administration. The expression of FSP1, GPX4, and PTGS2 (prostaglandin-endoperoxide synthase 2) was measured by Western blotting, immunohistochemistry and other methods. The correlation between FSP1 and ferroptosis and the role of FSP1 in COPD were explored by screening the expression of ferroptosis-related genes in a COPD cell model after the inhibition and overexpression of FSP1. We then explored the underlying mechanism of low FSP1 expression in patients with COPD by methylated RNA immunoprecipitation quantitative qPCR. We found that cigarette smoke exposure can lead to an increase in lipid peroxide production and ultimately ferroptosis, which is negatively regulated by FSP1 activity. FSP1 overexpression can prevent ferroptosis and alleviate emphysema. Next, we found that decreased FSP1 expression was caused by increased N6-methyladenosine modification of FSP1 mRNA. Moreover, the level of FSP1 decreased in a YTHDF2-dependent manner. These results indicate that METTL3-induced FSP1 mRNA methylation leading to low FSP1 expression is a potential therapeutic target for COPD.