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|a We recently identified upregulation of a novel aryl hydrocarbon receptor (AhR) target gene, stanniocalcin 2 (STC2), by an endogenous AhR agonist, cinnabarinic acid (CA). STC2 is a disulfide-linked homodimeric secreted glycoprotein that plays a role in various physiologic processes, including cell metabolism, inflammation, endoplasmic reticulum (ER) and oxidative stress, calcium regulation, cell proliferation, and apoptosis. Our previous studies have confirmed that CA-induced AhR-dependent STC2 expression was able to confer cytoprotection both in vitro and in vivo in response to injury induced by variety of ER/oxidative insults. Here, we used mouse models of chronic and acute ethanol feeding and demonstrated that upregulation of STC2 by CA was critical for cytoprotection. In STC2 knockout mice (STC2-/-), CA failed to protect against both acute as well as chronic-plus-binge ethanol-induced liver injury, whereas re-expression of STC2 in the liver using in vivo gene delivery restored cytoprotection against injury based on measures of apoptosis and serum levels of liver enzymes, underlining STC2's indispensable function in cell survival. In conclusion, the identification of STC2 as an AhR target gene receptive to CA-mediated endogenous AhR signaling and STC2's role in providing cytoprotection against liver injury represents a key finding with potentially significant therapeutic implications. SIGNIFICANCE STATEMENT: We recently identified stanniocalcin 2 (STC2) as a novel aryl hydrocarbon receptor (AhR) target gene regulated by endogenous AhR agonist and tryptophan metabolite, cinnabarinic acid (CA). Here, we showed that CA-induced STC2 expression conferred cytoprotection against apoptosis, steatosis, and liver injury in chronic as well as acute models of ethanol feeding. Therefore, this study will prove instrumental in developing CA as a promising lead compound for future drug development against hepatic diseases. Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics.
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