AIM2 Regulates Autophagy to Mitigate Oxidative Stress in Aged Mice with Acute Liver Injury

Abstract

Abstract Background: The cytoplasmic pattern recognition receptor absent in melanoma 2 (AIM2) detects cytosolic DNA and activates the inflammasome, resulting in the production of pro-inflammatory cytokines and inducing pyroptotic cell death. Recent research has highlighted AIM2's role in PANoptosis and host defence. Acute liver injury resulting from acetaminophen (APAP) overdose involves various critical events such as APAP metabolite protein adduct formation, mitochondrial dysfunction, oxidant stress, peroxynitrite formation, and nuclear DNA fragmentation. However, the role of AIM2 in APAP-induced hepatoxicity remains unclear. Results: we discovered that AIM2 negatively regulates the pathogenesis of liver damage induced by APAP in aged mice, independent of inflammasome activation. AIM2-deficient aged mice displayed increased lipid accumulation and hepatic triglycerides compared to wild-type mice. Moreover, AIM2 knockout mice with APAP overdose experienced more severe liver injury, worse mitochondrial stability, greater glutathione depletion, reduced autophagy, and higher levels of phosphorylated c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK). Additionally, we found that AIM2 localizes in mitochondria and its overexpression in mouse hepatocytes enhances autophagy while reducing JNK phosphorylation. Notably, induction of autophagy through rapamycin administration reduced serum alanine aminotransferase levels and the necrotic liver area in AIM2-deficient aged mice with APAP overdose. Mechanistically, AIM2 deficiency promoted acute liver damage induced by APAP and an inflammatory response by increasing oxidative stress and the phosphorylation of JNK and ERK in aged mice. Conclusions: AIM2 regulates autophagy and lipid peroaxidation, making it a promising therapeutic target for the treatment of age-related acute liver damage.