Abstract 1533: Regulatory mechanism of bile acid-induced hepatokine ORM2 expression and its implication in the liver cancer

Abstract Bile acids (BAs) are increasingly recognized as key signaling molecules with various metabolic effects in diverse pathophysiologic contexts. Uncontrolled BA synthesis or impaired BA flow leads to cholestasis, a severe liver disease, characterized by extensive hepatic damage and progression to liver failure or liver cancer. The nuclear receptors (NRs) farnesoid X receptor (FXR) and small heterodimer partner (SHP) play critical roles in maintaining BA homeostasis; consequently, FXR/SHP double knockout mice (FS-DKO) exhibit juvenile onset cholestasis that ultimately develops liver cancer. We recently identified orosomucoid 2 (ORM2) a novel liver-secreted hormone (i.e., hepatokine), which is highly induced in response to hepatic BA stress. In this study, we identified the molecular mechanism underlying BA-induced Orm2 transcription, potentially mediated by activation of the xenobiotic NRs, constitutive androstane receptor (CAR) and pregnane X receptor (PXR). BA supplementation directly upregulated Orm2 expression whereas it was completely abolished in CAR/PXR double knockout livers. Given the diverse roles of BAs and ORM2 in metabolic and carcinogenic processes, our study highlights that BA stress activates CAR and PXR to induce ORM2 expression, which initially exerts a protective function in acute liver injury but eventually promotes liver cancer. These insights suggest a potential link between hepatic BA signaling, CAR/PXR activation, and systemic outcomes in the pathology from cholestasis to liver cancer. Citation Format: Ji Ho Suh, Inyoung Cheon, Hyun-Jung Jung, Sung Ho Lee, Mi Jeong Heo, Matthew DeBerge, Clavia Ruth Wooton-Kee, Young-Ho Ahn, Kang Ho Kim. Regulatory mechanism of bile acid-induced hepatokine ORM2 expression and its implication in the liver cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1533.