RNA-m6A modification of HDGF mediated by Mettl3 aggravates the progression of atherosclerosis by regulating macrophages polarization via energy metabolism reprogramming

Macrophage polarization plays a crucial role in atherosclerosis (AS), which is closely associated with energy metabolism. However, the underlying mechanism remains elusive. Hepatoma-derived growth factor (HDGF) has been reported to promote tumor metastasis via energy metabolism reprogramming. In this study, we aimed to investigate the role and underlying mechanism of HDGF in regulating macrophage polarization and AS. Our results suggested the elevated expression of HDGF in aortas from atherosclerotic patients and Apoe^KO mice, as well as M1 macrophages. The specific deficiency of HDGF in macrophages resulted in a significant reduction of plaque area, inflammation and M1 macrophages content in Apoe^KO mouse model of AS. Consistent with the in vivo data, the specific deficiency of HDGF attenuated the inflammation, glycolysis, and lipids accumulation in M1 macrophages, and rescued the mitochondrial dysfunction. Mechanistically, HDGF plays a crucial role in atherogenesis by regulating the M1 macrophages polarization through energy metabolism reprogramming. The expression level of methyltransferase Mettl3 elevated significantly in M1 macrophages, which contributed to enhancing mRNA stability and protein expression of HDGF via N⁶-methyladenosine (m6A) RNA methylation. Taken together, our study revealed a novel mechanism underlying the macrophage polarization, which may be a potential therapy for AS.