TGM3 (transglutaminase 3) catalyzes calcium-dependent isopeptide cross-linking between glutamine and lysine residues in proteins and mediates polyamine conjugation 1. In normal physiology, TGM3 functions as a pro-enzyme activated by proteolysis, primarily expressed in terminally differentiating epidermal and hair follicle keratinocytes 2. It catalyzes cross-linking of small proline-rich proteins (SPRR1/SPRR2) and loricrin to form the cornified envelope, a critical component of the epidermal barrier 1. TGM3 also hardens the hair follicle inner root sheath through structural protein cross-linking 1. Despite its barrier-protective function, TGM3 exhibits complex, context-dependent roles in cancer. In head and neck cancer, TGM3 functions as a tumor suppressor—downregulated via promoter CpG hypermethylation, with low expression predicting worse survival 3. Similarly, in cutaneous squamous carcinoma, TGM3 acts as a differentiation marker and tumor suppressor via PI3K-AKT pathway inhibition and KRT14 degradation 4. However, in hepatocellular carcinoma, TGM3 is overexpressed and promotes epithelial-mesenchymal transition and poor prognosis 5. In metastatic contexts, TGM3 transamidates Exo70 to promote tumor cell migration and invasion, opposed by LKB1-mediated phosphorylation 6. Pan-cancer analyses reveal TGM3 as a prognostic biomarker correlating with clinical stage and inversely with immune infiltration 7. Mutations in TGM3 cause uncombable hair syndrome 2, emphasizing its structural protein function 1.