OGG1 Stimülasyonu Oksidatif DNA Hasarı Onarımını İyileştirir ve Asetaminofen Kaynaklı Akut Karaciğer Yetmezliğine Karşı Korur

Özet (abstract)

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.

Yazarların özeti; kaynağından alınmıştır. Advanced Science, 2026 · DOI ↗