GGH (gamma-glutamyl hydrolase) is a folate metabolism enzyme that hydrolyzes polyglutamylated folates into monoglutamate forms, playing a key role in folate bioavailability and the cellular disposition of antifolate drugs like methotrexate (MTX). Beyond its canonical enzymatic function, GGH acts as a non-canonical RNA-binding protein that stabilizes cell-cycle and DNA-replication mRNAs such as CDC6 and CCND1 through interaction with the GC-rich motifs in their 5′ untranslated regions 1. GGH forms a ternary complex with the RNA-binding protein HuR to enhance mRNA stability, supporting its oncogenic role in lung cancer 1. GGH silencing inhibits lung cancer cell growth and induces autophagic cell death by increasing folate stress and elevating the NADH/NAD+ ratio, which activates AMPK-mediated autophagy 2. Clinically, GGH polymorphisms influence MTX pharmacogenetics in patients with hematological malignancies and childhood acute lymphoblastic leukemia; the GGH rs3758149 TT genotype associates with gastrointestinal and hepatic toxicity, while the C allele correlates with better treatment response 3 4. Elevated GGH expression in lung cancer tissues correlates with poor patient survival, suggesting GGH represents a therapeutic target for cancer prevention and treatment 1.