A new mouse model of radiation-induced liver disease reveals mitochondrial dysfunction as an underlying fibrotic stimulus Authors Nicolas Melin, Tural Yarahmadov, Daniel Sanchez-Taltavull, Fabienne E. Birrer, Tess M. Brodie, Benoît Petit, Andrea Felser, Jean-Marc Nuoffer, Matteo Montani, Marie-Catherine Vozenin, Evelyn Herrmann, Daniel Candinas, Daniel M. Aebersold, Deborah Stroka Correspondence deborah.stroka@dbmr.unibe.ch (D. Stroka). Graphical abstract Irradiation mtDNA damage mtDNA mutations mitochondrial ETC dysfunction mtROS antioxidant exhaustion Liver SOS FIBROSIS Lipid peroxides p53 Senescence Normal liver Highlights  New mouse model of radiation-induced liver fibrosis using image-guided radiation.  Irradiated tissue develops pericentral fibrosis 6 weeks post-irradiation.  Irradiation induces hepatic mitochondrial DNA mutagenesis.  Hepatocyte irradiation provokes mitochondrial dysfunction.  Irradiation increases ROS, p53 and senescence signaling leading to hepatic fibrosis. Lay summary Irradiation is an efficient cancer therapy, however, its applicability to the liver is limited by life-threatening radiation-induced hepatic fibrosis. We have devel- oped a new mouse model of radiation-induced liver fibrosis, that recapitulates the human disease. Our model highlights the role of mitochondrial DNA instability in the development of irradiation-induced liver fibrosis. This new model and subsequent find- ings will help increase our understanding of the he- patic reaction to irradiation and to find strategies that protect the liver, enabling the expanded use of radio- therapy to treat hepatic tumors. https://doi.org/10.1016/j.jhepr.2022.100508 Research article