Nobiletin ameliorates alcohol-related liver disease through Ephx1 or Sult1a1- involved mechanisms

Nobiletin (NOB), a natural polymethoxylated flavonoid derived from plants, exhibits potential as a hepatoprotective agent, however, its mechanism in Alcohol-associated liver disease (ALD) remains incompletely understood. It has been observed that lipid metabolism, alcohol metabolism, and gut microbiota play crucial roles in the pathogenesis of ALD. This study aims to evaluate the impact of NOB on ALD and elucidate its underlying mechanisms. Using the Lieber-DeCarli liquid alcohol diet, an ALD model was established in C57BL/6J mice. Following five weeks of intervention, it was discovered that NOB significantly attenuated alcohol-induced hepatic steatosis and liver damage while also rectifying disturbances in lipid metabolism-related genes and oxidative stress imbalance. Liver transcriptomic sequencing and qPCR validation revealed that NOB intervention effectively reversed the expression of 16 genes disrupted by alcohol exposure. Among these genes, Ephx1 and Sult1a1 were notably upregulated in the liver and hepatocytes following alcohol treatment. Spearman correlation analysis indicated a positive association between Ephx1 and Sult1a1 expression and markers of hepatic steatosis, liver injury, and oxidative stress. Vitro experiments demonstrated that knocking down Ephx1 and Sult1a1 alleviated alcohol-induced injury, intracellular lipid accumulation, and dysregulation of lipid metabolism-related genes, suggesting Ephx1 and Sult1a1 involvement in NOB protective mechanism against ALD. In conclusion, our findings suggest that targeted interventions can mitigate liver dysfunction caused by chronic alcohol consumption by targeting specific molecular factors such as Ephx1 and Sult1a1, as well as by modulating gut microbiota composition to improve ALD.