BACKGROUND M1 polarization of macrophages is an important pathological process in myocardial ischemia reperfusion injury,which is the major obstacle for the treatment of acute myocardial infarction.Currently,the strategies and mechanisms of inhibiting M1 polarization are poorly explored.This study aims to investigate the role of soluble death receptor 5-Fc (sDR5-Fc) in regulating M1 polarization of macrophages under extreme conditions and explore the mechanisms from the aspect of glycolysis.METHODS Extreme conditions were induced in RAW264.7 cells.Real-time quantitative polymerase chain reaction and western blot were used to detect the expression of mRNA and proteins,respectively.Cell counting kit-8 was used to investigate the proliferation activity of cells.Expression levels of inflammatory cytokines were determined by enzyme-linked immunosorbent assay.RESULTS We found that sDR5-Fc rescues the proliferation of macrophages under extreme conditions,including nutrition deftciency,excessive peroxide,and ultraviolet irradiation.In addition,administration of sDR5-Fc inhibits the M1 polarization of macrophages induced by lipopolysaccharide (LPS) and interferon-gamma (IFN-γ),as the expression of M1 polarization markers CD86,CXC motif chemokine ligand 10,matrix metalloproteinase 9,and tumor necrosis factor-α,as well as the secretion of inflammatory factors interleukin (IL)-1β and IL-6,were significantly decreased.By further investigation of the mechanisms,the results showed that sDR5-Fc can recover the LPS and IFN-γ induced pH reduction,lactic acid elevation,and increased expression of hexokinase 2 and glucose transporter 1,which were markers of glycolysis in macrophages.CONCLUSIONS sDR5-Fc inhibits the M1 polarization of macrophages by blocking the glycolysis,which provides a new direction for the development of strategies in the treatment of myocardial ischemia reperfusion injury.