Mitochondrial topoisomerase I (Top1MT) prevents the onset of metabolic dysfunction-associated steatohepatitis (MASH) in mice.

High fat (HF) diet is a major factor in the development of metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatis (MASH), and mitochondria have been proposed to play a role in the pathogenesis of HF diet-induced MASH. Because Mitochondrial topoisomerase I (Top1MT) is exclusively present in mitochondria and Top1MT knock-out mice are viable, we were able to assess the role of Top1MT in the development of MASH. We show that after 16 weeks of HF diet, mice lacking Top1MT are prone to the development of severe MASH characterized by liver steatosis, lobular inflammation and hepatocyte damage. Mice lacking Top1MT also show prominent mitochondrial dysfunction, ROS production and mitochondrial DNA (mtDNA) release, accompanied by hepatic inflammation and fibrosis. In summary, our study demonstrates the importance of Top1MT in sustaining hepatocyte functions and suppressing MASH.