Tissue transglutaminase 2 (tTG2) is a multifunctional enzyme involved in extracellular matrix stabilization, cell adhesion, signal transduction, and protein crosslinking. It plays a pivotal role in various physiological processes, but its dysregulation has been implicated in multiple diseases, including celiac disease, fibrosis, cancer, and neurodegenerative disorders. Due to its involvement in disease progression, tTG2 is a prime target for drug discovery, yet the development of small-molecule inhibitors remains an underexplored frontier.