Role of ERK1/2 Signaling in Cinnabarinic Acid-Driven Stanniocalcin 2-Mediated Protection against Alcohol-Induced Apoptosis

J Pharmacol Exp Ther. 2023 Oct;387(1):111-120. doi: 10.1124/jpet.123.001670. Epub 2023 Aug 10.


We have previously shown that a bona fide aryl hydrocarbon receptor (AhR) agonist, cinnabarinic acid (CA), protects against alcohol-induced hepatocyte apoptosis via activation of a novel AhR target gene, stanniocalcin 2 (Stc2). Stc2 translates to a secreted disulfide-linked hormone, STC2, known to function in cell development, calcium and phosphate regulation, angiogenesis, and antiapoptosis-albeit the comprehensive mechanism by which the CA-AhR-STC2 axis confers antiapoptosis is yet to be characterized. In this study, using RNA interference library screening, downstream antiapoptotic molecular signaling components involved in CA-induced STC2-mediated protection against ethanol-induced apoptosis were investigated. RNA interference library screening of kinases and phosphatases in Hepa1 cells and subsequent pathway analysis identified mitogen-activated protein kinase (MAPK) signaling as a critical molecular pathway involved in CA-mediated protection. Specifically, phosphorylation of ERK1/2 was induced in response to CA treatment without alterations in p38 and JNK signaling pathways. Silencing Stc2 in Hepa1 cells and in vivo experiments performed in Stc2-/- (Stc2 knockout) mice, which failed to confer CA-mediated protection against ethanol-induced apoptosis, showed abrogation of ERK1/2 activation, underlining the significance of ERK1/2 signaling in CA-STC2-mediated protection. In conclusion, activation of ERK1/2 signaling in CA-driven AhR-dependent Stc2-mediated protection represents a novel mechanism of protection against acute alcohol-induced apoptosis. SIGNIFICANCE STATEMENT: Previous studies have shown the role of stanniocalcin 2 (Stc2) in cinnabarinic acid (CA)-mediated protection against alcohol-induced apoptosis. Here, using RNA interference library screening and subsequent in vivo studies, the functional significance of ERK1/2 activation in CA-induced Stc2-mediated protection against acute ethanol-induced apoptosis was identified. This study is thus significant as it illustrates a comprehensive downstream mechanism by which CA-induced Stc2 protects against alcoholic liver disease.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Ethanol* / toxicity
  • Hepatocytes* / drug effects
  • Hepatocytes* / metabolism
  • Intercellular Signaling Peptides and Proteins
  • Liver / drug effects
  • Liver / physiopathology
  • Liver Diseases, Alcoholic* / drug therapy
  • Liver Diseases, Alcoholic* / genetics
  • Liver Diseases, Alcoholic* / metabolism
  • MAP Kinase Signaling System* / genetics
  • MAP Kinase Signaling System* / physiology
  • Mice
  • Oxazines* / pharmacology
  • Oxazines* / therapeutic use
  • Receptors, Aryl Hydrocarbon / agonists


  • cinnabarinic acid
  • Ethanol
  • Intercellular Signaling Peptides and Proteins
  • Stc2 protein, mouse
  • Oxazines
  • Receptors, Aryl Hydrocarbon