TMEM189/PEDS1 deficiency aggravates MASH progression by promoting FASN-mediated macrophage activation

Abstract Transmembrane protein 189 (TMEM189), also known as plasmanylethanolamine desaturase 1 (PEDS1), is involved in plasmalogen biosynthesis, phospholipid metabolism, ferroptosis, and autophagy. However, whether TMEM189/PEDS1 regulates macrophages and disease-related inflammatory responses remains unclear. Here, we for the first time investigated the contribution of TMEM189/PEDS1 to macrophage activation and progression of metabolic dysfunction-associated steatohepatitis (MASH). Experimental data demonstrated that TMEM189 is highly expressed in macrophages, and its inactivation promotes M1 macrophage polarization and increases lipid loading in co-cultured hepatocytes. Loss of Tmem189 in myeloid cells results in a selective increase in the population and activation of monocyte-derived macrophages (MDMs) in the liver, which exacerbates hepatic steatosis, inflammatory damage, and fibrosis in diet-induced MASH mice. The restoration of Tmem189 expression in hepatic macrophages significantly attenuates MASH-related phenotypes. Mechanistically, TMEM189 interacts with fatty acid synthase (FASN), negatively regulates its expression and pro-inflammatory response in macrophages. Further studies revealed that TMEM189 deletion enhances FASN-promoted NLRP3 palmitoylation and its activation, leading to increased IL-1β production, which in turn further accelerates MASH progression. Our findings provide important evidence supporting the critical regulatory role of TMEM189-FASN signaling in liver macrophage activation and MASH progression, which may represent a potential therapeutic target for MASH treatment.