Liver-specific knockout of CD73 exacerbated alcohol-associated steatohepatitis by regulating adenosine signalling and hepatic clock gene BMAL1.

Alcohol-associated liver disease (ALD) is a leading cause of morbidity and premature mortality worldwide, characterized by hepatic steatosis and inflammatory cell infiltration. CD73, predominantly expressed in hepatocytes, has been implicated in the regulation of hepatocyte metabolism and liver homeostasis. However, whether and how hepatocyte CD73 contributes to ALD pathogenesis remains poorly understood and warrants systematic investigation. In this study, we observed that CD73 expression was significantly upregulated in ethanol (EtOH)-exposed hepatocytes and in liver tissues from mice with alcohol-associated steatohepatitis (ASH). Liver-specific CD73 knockout (CD73-LKO) altered circadian locomotor activity, exacerbated EtOH-induced liver injury and inflammatory infiltration, and promoted hepatic fatty acid uptake and de novo lipogenesis in vivo. In vitro, CD73 knockdown in hepatocytes aggravated cellular injury, enhanced fatty acid synthesis, and increased lipid deposition, whereas CD73 overexpression conferred protective effects. Furthermore, we found that CD73 modulates the expression of adenosine receptors and circadian clock components. In primary hepatocytes from EtOH-fed mice, CD73-LKO upregulated A