Current insights on transglutaminase 2: Exploring its functions, mechanisms, and therapeutic potential in glioblastoma

Glioblastoma (GBM) is the most aggressive and lethal primary brain tumor in adults, marked by diffuse infiltration, extensive heterogeneity, and resistance to standard therapies. Despite advances in surgery, radiation, and chemotherapy, GBM remains incurable, with a median survival of ∼15 months. Tumor recurrence, driven by therapy-resistant glioma stem cells and adaptive molecular mechanisms, presents a significant challenge to treatment. Identifying regulators of GBM progression and resistance is crucial for developing more effective interventions. Transglutaminase 2 (TGM2), a ubiquitously expressed enzyme with both Ca 2+ ‐dependent and -independent activities, has emerged as a pivotal yet underexplored context-specific contributor to various malignancies. Aberrant TGM2 expression has been linked to hallmark features of GBM, including stemness, invasion, epithelial-to-mesenchymal transition, and chemo-radioresistance. However, its multifunctionality, conformational flexibility, and widespread subcellular localization have complicated efforts to delineate precise oncogenic mechanisms. Conflicting data suggest TGM2 may promote both survival and apoptosis, underscoring the need for nuanced investigation. This review provides an overview of TGM2’s structural features, biochemical functions, and regulatory mechanisms, with a focus on its role in GBM progression and resistance to chemo-radiotherapy. Emerging evidence implicates TGM2 in enhancing DNA repair, promoting cellular plasticity, and evading apoptosis, all of which contribute to tumor survival. Targeting TGM2 has shown promise in preclinical studies, especially inhibitors that exhibit the potential to cross the blood-brain barrier, addressing a major challenge in effective GBM therapy. By integrating molecular and translational insights, this review highlights TGM2 as a promising therapeutic target for overcoming resistance and advancing combined precision strategies for GBM treatment. Four structural domains contribute to the diverse functions and conformational states of transglutaminase 2 (TGM2). Small-molecule inhibitors (GK921, KCC009, ZED1227, Cystamine/MDC, LDN-27219) modulate function by targeting these distinct sites, while oxidative conditions promote a catalytically inactive open conformation. • TGM2 adopts different conformations, regulating enzymatic and signaling functions. • Ca 2+ or GTP binding, transcription, and redox state control TGM2 enzymatic activity. • Overexpression of TGM2 correlates with poor prognosis in patients with GBM. • Aberrant TGM2 promotes ECM remodeling, GBM tumor growth, and chemo-radioresistance. • Small molecule inhibitors of TGM2 show promise in overcoming therapeutic resistance.