Ethanolamine phosphate phospholyase drives non-alcoholic fatty liver disease via hepatocyte ferroptosis and ferroptosis-mediated macrophage reprogramming.

Obesity is closely linked to the development of non-alcoholic fatty liver disease (NAFLD), yet its mechanisms are not fully understood. Ethanolamine phosphate phospholyase (ETNPPL), an enzyme highly expressed in the liver, catalyzes the conversion of phosphoethanolamine to ammonia, inorganic phosphate, and acetaldehyde. This study shows that ETNPPL plays a crucial role in obesity-associated NAFLD by regulating lipid accumulation, liver dysfunction, and lipid homeostasis. ETNPPL expression was increased in high-fat diet (HFD)-induced NAFLD mice, while its deficiency alleviated NAFLD. ETNPPL overexpression and free fatty acids (FFAs) exposure promoted ferroptosis in hepatocytes. The FFAs-ETNPPL signaling axis induces lipid accumulation and dysfunction through ferroptosis via the GPX4/mtROS pathway and the inhibition of ALDH2. Moreover, FFAs-induced hepatocyte ferroptosis reprogrammed macrophages, exacerbating liver dysfunction. In vivo, ETNPPL knockout reduced hepatic ferroptosis and macrophage reprogramming in mice. These findings highlight ETNPPL as a potential therapeutic target for obesity-related NAFLD.