N6-(2-Hydroxyethyl) Adenosine Alleviates Hepatic Steatosis and Insulin Resistance by Inhibiting JunB+ Adipocytes

N6-(2-hydroxyethyl) adenosine (HEA), the main active component of Cordyceps species, has garnered attention for its multifaceted hypolipidemic and antihyperglycemic activities. However, the influence by which HEA affects the progression of nonalcoholic fatty liver disease (NAFLD) remains unclear. This study sought to investigate the efficacy and mechanisms of HEA in treating NAFLD. The mouse NAFLD models were induced by high-fat diet feeding or methionine-choline-deficient diet feeding. AML12 and HepG2 cells were used for the in vitro study. Lipidemic and glycemic parameters, untargeted lipidomic, cellular thermal shift assay, and so forth were used to explore the beneficial effects of HEA in NALFD. HEA effectively alleviated the progression of NAFLD by regulating glucolipid metabolism and insulin resistance both in vitro and in vivo. Lipidomic data suggested that HEA markedly reduced triglyceride levels by blocking hepatic de novo lipogenesis and shifting fatty acids into mitochondria for oxidation and into structural lipids. Moreover, stimulation of the supernatant of adipocytes with HEA was more effective than treatment with HEA only in terms of hepatic de novo lipogenesis in HepG2 cells. Mechanistically, HEA significantly reduced the population of JunB+ adipocytes, which exerts lower thermogenic capacity. Further studies verified that HEA interacted with ASP-12, ASP-13, and TYR-15 of JunB subunits through hydrogen bonding, leading to activated PGC-1α activity and governing thermogenic adipocyte heterogeneity and consequent biological responses. These findings highlight the capacity of HEA to alleviate NAFLD through the JunB pathway, paving a new way to treat NAFLD by influencing adipocyte functionality.