GGH (gamma-glutamyl hydrolase) is a folate-metabolizing enzyme that hydrolyzes polyglutamylated folates into monoglutamate forms, playing a critical role in folate bioavailability and metabolism 12. The enzyme progressively removes gamma-glutamyl residues from pteroylpolyglutamate to yield folic acid and free glutamate, functioning as a lysosomal glycoprotein that reduces intracellular folate stress 3. Beyond its canonical enzymatic function, GGH exhibits a non-canonical role as an RNA-binding protein that stabilizes cell cycle and DNA replication mRNAs, including CDC6 and CCND1 4. GGH directly interacts with HuR, a well-characterized RNA-binding protein, forming ternary complexes that enhance mRNA stability and promote tumor progression 4. Clinically, GGH polymorphisms significantly influence methotrexate (MTX) pharmacogenetics. The GGH rs3758149 TT genotype associates with gastrointestinal and hepatic toxicity, while both FPGS rs1544105 C allele and GGH rs3758149 TT genotype correlate with improved remission in hematological malignancies 5. In pediatric acute lymphoblastic leukemia, GGH variant haplotypes improve event-free survival and reduce relapse rates compared to wild-type carriers 6. GGH is highly expressed in lung cancers, correlating with worse patient survival, making it a potential therapeutic target 4. GGH silencing induces autophagic cell death through elevated folate stress and NADH-mediated AMPK activation 3.