TGM1 (transglutaminase 1) catalyzes protein cross-linking and polyamine conjugation, primarily functioning in epidermal barrier formation 123. It cross-links epidermal proteins during stratum corneum formation and promotes keratinocyte proliferation and differentiation 34. TGM1 is critical for cornified envelope assembly and maintaining skin barrier integrity 5. Mechanistically, TGM1 operates through transamidation reactions. Recent evidence reveals that TGM1 transamidates Exo70 with cystatin A, promoting tumor cell motility and extracellular matrix remodeling—a process inhibited by the tumor suppressor LKB1 6. TGM1 expression is regulated by mitogen-activated protein kinase signaling pathways and associated with GF-RTK-PI3K and JAK-STAT signaling 7. Clinically, TGM1 mutations cause autosomal recessive congenital ichthyosis type 1 (ARCI), characterized by severe skin barrier dysfunction 8. TGM1 variants are associated with collodion membrane at birth, alopecia, hearing problems, and eye abnormalities in ichthyosis patients 9. Beyond monogenic disease, TGM1 functions as a signature gene in psoriasis, where elevated expression increases inflammatory cytokine production and keratinocyte differentiation markers 7. Pan-cancer analysis indicates TGM1 has prognostic significance and immunomodulatory roles in multiple malignancies 10. Gene therapy approaches using retroviral vectors effectively restore TGM1 expression in patient-derived keratinocytes, restoring barrier function 5.