TGM2 (transglutaminase 2) is a multifunctional enzyme with transglutaminase crosslinking, GTP binding, and kinase activities that regulates diverse cellular processes including apoptosis, gene transcription, and DNA repair 1. Mechanistically, TGM2 catalyzes histone serotonylation at H3Q5, a post-translational modification that enhances TFIID binding to H3K4me3-marked nucleosomes and promotes permissive gene expression 2. In cancer contexts, TGM2 drives malignant progression through distinct mechanisms: in hepatocellular carcinoma via MYC pathway activation 3, in gastric cancer by suppressing STAT1 ubiquitination through GTP-binding activity 4, and in glioblastoma by promoting autophagosome-lysosome fusion to enhance radioresistance 5. Additionally, TGM2-mediated histone serotonylation orchestrates neutrophil extracellular trap formation, facilitating neuroendocrine cancer liver metastasis 6. Clinically, TGM2 expression correlates with poor prognosis and serves as a therapeutic target; TGM2 inhibition suppresses tumor progression and synergizes with standard therapies including sorafenib and ionizing radiation 37. TGM2 is also identified as a candidate frailty biomarker in aging-related pathologies 8. Alternative splicing of TGM2 produces functionally distinct isoforms 1, contributing to its roles across cancer, neurodegeneration, inflammation, and wound healing.