Authors
Zhenjun Zhao, Rahul Upadhyay, Alice Eddershaw, Chenchen Wang, Yudong Zhao, Olov Wallner, Jinhye Ryu, Nayere Taebnia, Heather Gildie, Emma Scaletti-Hutchinson, Jonathan R Davies, Nicole Ziegler, Andreas Krämer, Samantha C Robinson, Marek Varga, Karolina Singerova, Zuzanna Szaruga, Elisée Wiita, İrşil Güneş, Sheila S David, Stefan Knapp, Aimo Kannt, Miguel de Vega, Pål Stenmark, Volker M Lauschke, Maurice Michel
Published in
Advanced science (Weinheim, Baden-Wurttemberg, Germany). Pages e77956. Sep 27, 2026. Epub Sep 27, 2026.
Abstract
Acetaminophen-induced acute liver failure is characterized by reactive metabolite formation, resulting in profound oxidative stress and mitochondrial dysfunction, leading to oxidative DNA damage and loss of hepatocyte viability. While oxidative stress is well recognized as a central pathogenic driver, the contribution of DNA damage resolution pathways to hepatocyte survival remains poorly defined. Here we report the development of a small molecule, CMM-98, that installs a robust AP-site processing function in the DNA glycosylase OGG1 by binding the active site. Acting on the Schiff base intermediate, the molecule effectively rewires the enzyme's catalytic outcome under oxidative stress, boosting AP site turnover by 57-fold. Using cellular and in vivo models of acetaminophen-induced liver failure, we demonstrate that OGG1 catalysis manipulated by CMM-98 reduces oxidative DNA damage burden, promotes the resolution of oxidative DNA lesions, and ameliorates hepatocyte injury. These findings identify DNA repair capacity as a modifiable determinant of acute liver injury outcome and establish chemical switching of OGG1 as a strategy to support hepatocyte resilience under extreme oxidative stress.
PMID:
42801551
Bibliographic data and abstract were imported from PubMed on 28 Sep 2026.
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