Role of NADPH oxidases and NFκB signaling in mediating cancerogenic iron overload in alcoholic liver disease (ALD)

• Applicant: Professor Dr. Sebastian Mueller, since 3/2020
• Subject Area: Gastroenterology
• Term: since 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 270989511

Alcoholic liver disease (ALD) is the most common liver disease worldwide and accounts for about half of all primary liver cancers (HCC). Ca. 50% of all ALD patients show hepatic iron overload, which has been identified as independent risk factor for HCC development and survival. Iron itself is highly cancerogenic especially in an oxidative environment such as found in ALD. So far, the regulation of the iron master switch hepcidin as well as possible cellular cross talks influencing hepcidin expression are not fully understood and controversies remain on the role of oxidative stress. Beside acetaldehyde metabolism per se, NADPH oxidases (NOX) are a major producer of endogenous reactive oxygen species (ROS) leading to the end product hydrogen peroxide (H2O2). NOX are found to play a key role in (liver) fibrogenesis and first data from our team indicate a new potential role as upstream regulators of hepcidin. The proposal aims to determine the role of NOX-induced cell-type specific (hepatocyte and macrophage) signaling and subsequent hepatic hepcidin regulation, especially the involvement of the NFκB signaling pathway. These studies are further aimed to clarify the role of NOX-induced changes in hepcidin signaling eventually leading to iron overload in ALD. It is expected that the elucidation of the underlying molecular mechanisms of disturbed iron homeostasis in ALD will provide new treatment options for targeted therapies in patients at high risk.

• DFG Programme: Research Grants
• Ehemalige Antragstellerin: Vanessa Rausch, Ph.D., until 3/2020