The A3 adenosine receptor agonist, namodenoson, ameliorates non‑alcoholic steatohepatitis in mice
The Wnt/β-catenin pathway initiates a series of molecular events in livers affected by non-alcoholic steatohepatitis (NASH). Namodenoson, a selective agonist of the A3 adenosine receptor (A3AR) which is highly expressed in pathological liver cells, induces a strong anti-inflammatory effect in the liver by deregulating the Wnt/β-catenin pathway. Additionally, Namodenoson protects the liver by inhibiting ischemia/reperfusion injury. Given these properties, we investigated the anti-NASH effects of Namodenoson in murine models of steatohepatitis and the LX2 human hepatic stellate cell line (HSC). In the STAM model, Namodenoson significantly reduced the non-alcoholic fatty liver disease (NAFLD) activity score (NAS), demonstrating anti-inflammatory and anti-steatotic effects. In the carbon tetrachloride (CCl4) model, Namodenoson normalized alanine aminotransferase (ALT) levels and significantly improved liver inflammation, fibrosis, and adiponectin and leptin levels. Namodenoson deregulated the Wnt/β-catenin pathway in liver extracts from the CCl4 model mice and LX2 HSCs, shown by decreased expression of phosphoinositide 3-kinase (PI3K), nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB), β-catenin, lymphoid enhancer-binding factor 1 (Lef-1), and cyclin D1, alongside increased expression of glycogen synthase kinase 3β (GSK-3β). The fibrosis marker α-smooth muscle actin (α-SMA) was also downregulated, supporting Namodenoson’s anti-fibrotic effect. Overall, these findings demonstrate that Namodenoson exerts an anti-NASH effect through deregulation of the PI3K/NF-κB/Wnt/β-catenin signaling pathway. Thus, targeting A3AR may offer a novel approach in the pharmacotherapy of NAFLD/NASH.