Role of interferon signaling in hepatocyte senescence and metabolic changes in MASH and MASH-HCC

• Applicant: Lucía Alcober Boquet, Ph.D.
• Subject Area: Cell Biology ; Endocrinology, Diabetology, Metabolism
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 552374331

Fatty liver disease is a global health concern due to its high incidence. Its severe and inflammatory form, termed steatohepatitis, increases the likeness of cancer development. While steatohepatitis increases tumorigenesis, it also conversely favours the establishment of cellular senescence, a generally tumor-suppressing mechanism that limits further cellular division. The exact mechanism behind these seemingly contradictory effects and their consequence remains unexplored, constituting one of the underlying questions of the proposed project. Apart from its protective role in limiting cancer development, previous studies in the proposed host institution suggest that senescence also produces profound metabolic alterations in hepatocytes, including insulin resistance. These changes correlate with systemic morbidity such as cardiovascular diseases and are a key finding in patients with steatohepatitis. Therefore, the induction hepatic senescence may constitute a double-edged sword, preventing malignant transformation by upholding cell cycle fidelity, but potentially augmenting metabolic, clinically relevant comorbidities. It is therefore of great interest to understand the mechanism behind such metabolic alterations to develop therapies that uphold anti-tumorigenic properties but target the disadvantageous metabolic dysbalance. Recently, IGS15, an interferon inducible ubiquitin-like protein, has been linked to the conflicting programs of both cellular senescence and cancer development in different models. Furthermore, its previously proposed regulation of key metabolic pathways in line with the host institution’s findings render it an interesting target for further mechanistical studies in fatty liver disease that are proposed herein. The aim of this project is to interrogate the role of ISG15 in steatohepatitis, its associated metabolic dysregulation, and progression to liver cancer. The use of different knockout mouse strains and models of diet-induced disease will be combined to identify and functionally interrogate proteins which are modified by ISG15 - a posttranslational modification termed ISGylation. It is proposed that ISG15 critically shapes hepatocyte senescence. The effect of ISG15 on senescence-associated metabolic changes, such as global insulin resistance, will be investigated. This data should shed light into the mechanism behind metabolic aberrations in steatohepatitis and identify druggable targets to resolve hepatic insulin resistance without dismantling of generally favorable tumor suppressive characteristic of senescence. Thirdly, I will explore the role of ISG15 during HCC establishment and progression, focusing on understanding the seemingly contradictory effects ISGylation and how this contributes to the switch between senescence and cancer development.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Michael Karin, Ph.D.