Estrogen-related receptor gamma-Cytochrome P450 2E1 signaling pathway (ERRγ-CYP2E1)

The Estrogen-related receptor gamma (ERRγ) - Cytochrome P450 2E1 (CYP2E1) signaling pathway is a critical regulatory axis primarily implicated in the pathogenesis of alcohol-associated liver disease (ALD). ERRγ (encoded by the ESRRG gene) is an orphan nuclear receptor that functions as a constitutively active transcription factor, while CYP2E1 is a key enzyme in the microsomal ethanol oxidizing system responsible for ethanol metabolism and the generation of reactive oxygen species (ROS). Under conditions of chronic alcohol consumption, hepatic ERRγ expression is induced through the activation of cannabinoid receptor 1 (CB1), leading to the direct transcriptional upregulation of CYP2E1 via a conserved response element in its promoter [3, 6]. The resulting elevation in CYP2E1 activity causes excessive ROS production, oxidative stress, and hepatocyte apoptosis, which are hallmark features of oxidative liver injury [1, 9]. This pathway has become a focal point for therapeutic intervention; inverse agonists of ERRγ, such as GSK5182 and DN200434, have demonstrated the ability to suppress CYP2E1 induction and ameliorate liver damage in preclinical models [3, 4, 8]. Recent research also suggests that upstream regulators like Fibroblast Growth Factor 4 (FGF4) and RORα can repress this signaling axis, providing additional targets for mitigating alcohol-induced hepatotoxicity [1, 10].

Other names

ERRγ-CYP2E1 axisERRgamma-CYP2E1 pathwayEstrogen-related receptor gamma-Cytochrome P450 2E1 pathwayESRRG-CYP2E1 axis

Mechanism involves the inverse agonism of ERRγ to repress the transcription of the CYP2E1 gene, as well as the direct inhibition of the CYP2E1 enzyme to reduce the generation of reactive oxygen species [3, 6, 8]. Upstream modulation via FGF4 or RORα serves to increase the ubiquitination of ERRγ or switch its transcriptional mode to repression [1, 9].