Unraveling the role and mechanism of ferroptotic cell death in embryonically derived homeostatic Kupffer cells during NASH development

• Applicant: Dr. Janusz von Renesse
• Subject Area: General and Visceral Surgery
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 519224235

We hypothesize that the newly discovered programmed cell death mechanism ferroptosis is a central regulator of Kupffer cell loss during NASH development and that its inhibition can ameliorate NASH progression. Kupffer cells are key regulators of liver inflammation, and they maintain homeostasis. NASH development induces Kupffer cell loss and recruitment of monocyte-derived macrophages, which perpetuate inflammation and fibrosis. However, the underlying mechanism of Kupffer cell death remains elusive.Ferroptosis is a regulated cell death mechanism induced by iron-dependent lipid peroxidation. Accumulation of toxic lipid species is a hallmark of NASH, and elevated reactive oxygen species (ROS) levels are commonly found in affected livers. Kupffer cells are phagocytes scavenging large amounts of lipid-laden dying hepatocytes and can accumulate high iron loads due to their hemophagocytic role in iron metabolism. Importantly, in-vitro findings suggest a decreased ferroptosis sensitivity of inflammatory macrophages compared to alternatively activated macrophages. Based on these observations, we hypothesize that ferroptosis is a central mechanism responsible for the Kupffer cell loss present in NASH and that decelerating the loss of regulatory Kupffer cells might ameliorate NASH progression.Thus, to unravel the role of ferroptosis, its influence on the macrophage pool in NASH development, and the underlying metabolic pathways, we aim to answer the following three questions:● How susceptible are Kupffer cells to ferroptosis, and how does this susceptibility change with increasing steatosis and NASH development?● Can modulation of Kupffer cell ferroptosis attenuate the progression of NASH, and how does this intervention impact the immune infiltrate?● What metabolic pathways are activated in the NASH microenvironment that pave the way for ferroptosis induction?

• DFG Programme: WBP Fellowship
• International Connection: Switzerland
• Host: Professor Ping-Chih Ho, Ph.D.