GCDH Acetylation Orchestrates DNA Damage Response and Autophagy via Mitochondrial ROS to Suppress Hepatocellular...

Metabolic enzyme dysregulation promotes hepatocellular carcinoma (HCC) progression through metabolic reprogramming and lysine acetylation. Glutaryl-CoA dehydrogenase (GCDH), a key enzyme in lysine metabolism, has been demonstrated to play an essential role in modulating lysine crotonylation, which impacts the progression of HCC. However, the specific mechanisms by which GCDH influences lysine acetylation in HCC have not been completely clarified. In this study, GCDH was found to be acetylated at lysine 438 by acetyltransferase P300 and deacetylated by HDAC1. GCDH K438 acetylation was critical for its tumor-suppressive function in HCC cells. Overexpression of GCDH led to elevated levels of reactive oxygen species (ROS) and reduced oxidative phosphorylation (OXPHOS), thereby triggering ATR/Chk1-mediated DNA damage repair dysfunction and promoting autophagy in HCC cells. Furthermore, our investigation demonstrated that decreased GCDH expression was markedly associated with shorter overall survival in HCC patients and served as an independent prognostic indicator. Collectively, our findings demonstrate that the acetylation of GCDH at lysine 438 (K438), mediated by P300 and HDAC1, plays a vital role in the tumor-suppressive activities of HCC cells. GCDH inhibits HCC progression through ROS-mediated DNA repair dysfunction and autophagy.