Presentation description

Metabolic liver disease is a growing global health concern, especially as rates of obesity and diabetes rise in both older and younger populations. A severe form of this disease, called metabolic dysfunction-associated steatohepatitis (MASH), is marked by fat accumulation in the liver (steatosis), inflammation, and fibrosis. If left untreated, MASH can lead to liver failure. Despite its growing impact, most current treatments focus on lowering liver fat or slowing fibrosis, but these approaches often fail to prevent liver injury at the cellular level.

One key cellular defense system is the Integrated Stress Response (ISR), which helps cells adapt by reducing protein production and increasing protective genes. While this response is initially protective, chronic ISR activation can contribute to tissue damage. In MASH, mitochondrial stress is increasingly recognized as a key driver of hepatocyte injury. Mitochondria activate the ISR through a specific pathway involving DELE1 and its downstream kinase HRI (EIF2AK1). While the ER-linked ISR has been widely studied in liver disease, the role of this mitochondrial-specific DELE1-HRI pathway remains poorly understood.

In this project, we ask whether deleting HRI or DELE1 can protect the liver from injury in MASH. Using a mouse model that mimics human MASH with a high-fat, high-sugar diet and carbon tetrachloride exposure, we compare wild-type, HRI knockout, and DELE1 knockout mice. We assess liver health through serum biomarkers (ALT/AST), histology, and Western blotting for stress proteins such as eIF2α and ATF4. To explore underlying mechanisms, we also performed global proteomic analysis and RNA sequencing.

Preliminary data suggest that both HRI and DELE1 knockout mice exhibit reduced liver injury, including less steatosis and inflammation. These findings support the idea that mitochondrial ISR overactivation may worsen disease and highlight DELE1-HRI signaling as a promising target for future liver therapies.