Transglutaminase 2 (TGM2) is a ubiquitous and multifunctional calcium-dependent enzyme belonging to the transglutaminase family. It is best known for its canonical activity of catalyzing the cross-linking of proteins by forming stable ε-(γ-glutamyl)lysine isopeptide bonds, which contributes to extracellular matrix stabilization and wound healing. Beyond this, TGM2 exhibits GTPase activity, allowing it to function as a signaling G-protein in intracellular processes. It is implicated in a wide range of physiological functions, including cell adhesion, proliferation, and apoptosis, as well as pathological conditions such as celiac disease, fibrosis, neurodegenerative disorders, and cancer metastasis, where its dysregulated expression often contributes to disease progression.