From Gene to Enzyme: Multidimensional Decoding of the GGT Molecular Family and Its Clinical Tumor Diagnosis

ABSTRACT Background Gamma‐glutamyltransferase (GGT) is a membrane‐bound enzyme involved in glutathione metabolism and oxidative stress regulation. Although it is traditionally viewed as a liver function marker, emerging evidence suggests that its aberrant expression is closely associated with tumorigenesis, progression, and therapeutic resistance across multiple solid tumors. However, the comprehensive landscape of the GGT gene family and its clinical value in tumor diagnosis and prognosis remain unclear. Objective To systematically review the multidimensional roles of the GGT molecular family—including gene variants, mRNA isoforms, enzyme activity, and protein isoforms—in tumor biology and clinical oncology and to evaluate their potential as diagnostic and prognostic biomarkers. Methods We conducted a comprehensive literature review (PubMed, CNKI; inception–August 2025) focusing on (1) GGT family gene structure, expression patterns, and regulatory mechanisms; (2) GGT mRNA splice variants and isoforms; (3) GGT enzymatic activity and posttranslational modifications; and (4) clinical studies evaluating GGT as a biomarker in solid tumors. Data were synthesized narratively, emphasizing molecular mechanisms and clinical significance. Results The human GGT family comprises 13 homologous genes (e.g., GGT1‐7 and GGTLC1‐3) localized on chromosomes 20 and 22, which exhibit tissue‐specific expression and functional diversity. GGT1 (22q11.23), which is the most extensively studied gene, is highly expressed in renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), gastric cancer (GC), and breast cancer (BRC) and is correlated with poor prognosis and metastasis. GGT5 acts as a tumor suppressor in HCC but promotes progression in gastric cancer via PI3K/AKT pathway activation. GGT7 overexpression predicts poor survival in patients with HCC and glioblastoma. The GGT‐II isoform demonstrated 78.7% sensitivity and 92.3% specificity for HCC diagnosis, outperforming AFP (AUC: 0.89 vs. 0.67). Serum GGT activity ≥ 50 U/L independently predicts poor overall survival (OS) in patients with HCC (HR: 1.78, 95% CI: 1.26–2.50). GGT mRNA splice variants (e.g., the GGT‐I mRNA‐B subtype) enhance early HCC detection when combined with AFP (sensitivity: 98%). Conclusions The GGT molecular family plays pleiotropic roles in tumor biology via redox homeostasis, EMT, and immune modulation. The GGT1/5/7 and GGT‐II isoforms represent promising biomarkers for early diagnosis, prognosis, and therapeutic targeting in multiple cancers. Future multicenter studies should validate GGT‐based biomarker panels and elucidate the mechanisms underlying tissue‐specific GGT functions.