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

Mar 16, 2026International journal of biological macromolecules

Removing CD73 in the liver may worsen alcohol-related liver inflammation by affecting adenosine signals and the liver’s internal clock gene BMAL1

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Abstract

CD73 expression was significantly upregulated in ethanol-exposed hepatocytes and liver tissues from mice with alcohol-associated steatohepatitis.

Liver-specific knockout of CD73 altered circadian activity and worsened ethanol-induced liver injury and inflammation.
CD73 knockout in hepatocytes increased fatty acid synthesis and lipid deposition, indicating a role in liver metabolism.
Adenosine receptor signaling was found to regulate the expression of the core circadian clock gene BMAL1 in ethanol-stimulated liver cells.
Knockout of BMAL1 in the liver further exacerbated liver injury and steatosis in ethanol-fed mice.
These findings suggest that CD73 may influence liver health through its regulation of adenosine receptors and circadian rhythms.

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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 AR and AR protein levels, downregulated AR expression, and concurrently suppressed the core clock gene BMAL1. Notably, adenosine receptor signaling regulated BMAL1 expression in EtOH-stimulated AML-12 cells. Furthermore, liver-specific knockout of BMAL1 (BMAL1-LKO) aggravated liver injury and steatosis in EtOH-fed mice. In vitro, BMAL1 knockdown promoted lipid accumulation and cellular damage, while BMAL1 overexpression alleviated these pathological phenotypes. Collectively, these findings demonstrated that CD73-LKO could affect mice circadian rhythm, regulate the expression of liver adenosine receptors and BMAL1, which provides new insights into the molecular mechanisms underlying the role of CD73 in ALD. 1 2b2a

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

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