Researchers at Karolinska Institutet have developed a molecule that strengthens cells’ ability to repair oxidative DNA damage. In mouse models of acute liver failure, the molecule reduced liver damage and improved survival, while cultured human liver cells became more resistant to injury caused by paracetamol. The findings are published in Advanced Science.
Acute liver failure is a life-threatening condition in which liver cells are rapidly lost. One of the most common causes is an overdose of paracetamol, which can trigger extensive oxidative stress, damage DNA and impair mitochondria, the structures that produce energy in cells.
In the study, the researchers developed a compound called CMM-98 that enhances the activity of OGG1, an enzyme involved in repairing oxidative DNA damage. Laboratory experiments showed that the molecule enhanced a key step in DNA repair, helping cells clear certain forms of oxidative DNA damage more efficiently.
In liver cells exposed to oxidative stress, CMM-98 accelerated DNA repair and helped preserve mitochondrial structure.
Less liver damage
In a mouse model of acute liver failure caused by paracetamol, treatment with CMM-98 reduced oxidative stress, limited liver damage and improved survival. The researchers also observed protective effects when the compound was administered after paracetamol exposure, suggesting that enhancing DNA repair may be relevant even after liver injury has begun.
“Most treatments for acute liver failure aim to limit the damage to the liver. Our findings suggest that helping cells repair DNA damage could be another way of protecting liver cells during severe oxidative stress,” says Maurice Michel , researcher at the Department of oncology-pathology , Karolinska Institutet, and the study’s senior author.
The researchers also tested CMM-98 in three-dimensional cultures of primary human liver cells. The compound improved cell viability following paracetamol exposure and was associated with changes in cell signalling linked to adaptive stress responses.
The study was conducted in collaboration with researchers from Sweden, China, Germany and the United States. It was funded by several Swedish and international research funders, including the Novo Nordisk Foundation and the Swedish Research Council. Any potential conflicts of interest are disclosed in the published study.
Publication
Zhao Z, Upadhyay R, Eddershaw A, Wang C, Zhao Y, Wallner O, Ryu J, Taebnia N, Gildie H, Scaletti-Hutchinson E, Davies JR, Ziegler N, Krämer A, Robinson SC, Varga M, Singerova K, Szaruga Z, Wiita E, Güneş İ, David SS, Knapp S, Kannt A, de Vega M, Stenmark P, Lauschke VM, Michel M
Adv Sci (Weinh) 2026 Sep;():e77956
