SMAD4 is a central mediator of TGF-β signaling that functions as a tumor suppressor through transcriptional regulation 1. As a common SMAD (co-SMAD), it forms heterotrimeric complexes with receptor-activated SMADs (SMAD2/3 or SMAD1/5/8) in the nucleus, where it binds DNA at SMAD binding elements to regulate gene expression 2. SMAD4 mediates both proliferation and apoptosis in response to TGF-β signaling 3. Beyond canonical pathways, SMAD4 exhibits TGF-β-independent functions, including sequestration of NFATc1 in a phosphorylation-dependent manner, thereby suppressing NFATc1-driven transcriptional programs 4. SMAD4 inactivation is particularly prevalent in pancreatic cancer, occurring in approximately 50% of advanced cases through either homozygous deletion at 18q21.1 or intragenic mutations 2, with immunohistochemistry showing nuclear and cytoplasmic localization in normal tissue but loss in malignant tissue 5. SMAD4 mutations also cause hereditary conditions including juvenile polyposis syndrome, often with hereditary hemorrhagic telangiectasia (JP-HHT), affecting gastrointestinal and vascular development 6. De novo SMAD4 mutations in the MH2 domain cause Myhre syndrome, a developmental disorder characterized by skin thickening, joint limitation, and muscular pseudohypertrophy, involving impaired transcriptional regulation of TGF-β target genes 7. SMAD4 mutations also predispose to colorectal and prostate cancers 8.