Silencing GGH induces autophagy by increasing folate stress and production of NADH

There is an inextricable link between metabolic disorders and autophagy. Gamma-glutamyl hydrolase (GGH) is a lysosomal glycoprotein that reduces intracellular folate stress by catalyzing the hydrolysis of polyglutamylated folate into transportable monoglutamate. The relationship between folate metabolism, involving the folate metabolic enzyme GGH, and autophagy has rarely been reported. In this study, we found that GGH functions as a crucial oncogene in lung adenocarcinomas. Importantly, we found that cell autophagy and autophagic cell death are induced by GGH silencing through the elevated folate stress resulting from folate metabolism and the folate metabolite nicotinamide adenine dinucleotide (NADH). By increasing the NADH/NAD+ ratio, silencing GGH activates adenosine monophosphate-activated protein kinase (AMPK) through the activation of LKB1 and CAMKK2, as well as enhanced AMP/ATP and ADP/ATP ratios, which then triggers the initiation of early autophagy, finally resulting in autophagic cell death. Taken together, our study suggests that GGH may not only serve as a prognostic marker but also play a critical role in the initiation of early autophagy. Interventions targeting GGH to regulate folate metabolism and the proportion of NADH/NAD+ may have translational potential for precision therapy in human cancer.