SMAD3 is a receptor-regulated SMAD protein that serves as a central intracellular signal transducer activated by TGF-β and activin type 1 receptor kinases 1. Upon phosphorylation at its C-terminal residues, SMAD3 forms complexes with SMAD4 and other transcription factors to regulate target gene expression 2. SMAD3 activation can occur through multiple mechanisms: TGF-β receptor-mediated phosphorylation, EZH2-triggered K53/K333 methylation facilitating membrane recruitment, and activin A signaling in a TGF-β-independent manner 32. In cancer pathology, SMAD3 hyperactivation promotes metastasis through upregulation of Snail and Slug via MPS1-dependent phosphorylation, correlating with poor survival outcomes 43. SMAD3 also mediates chemoresistance in colorectal cancer by suppressing ferroptosis-related genes like ATF3 while inducing SLC7A11 5. Conversely, inhibiting SMAD3 phosphorylation reduces gluconeogenesis and hepatic fibrosis by attenuating the TGF-β1/SMAD3 pathway 1. In innate immunity, activin A-mediated SMAD3 activation in macrophages suppresses inflammation by controlling ATP-derived adenosine production, providing a natural brake against sepsis and psoriasis 2. SMAD3 dysfunction associates with Loeys-Dietz syndrome 3, osteoarthritis susceptibility 6, and vascular aging, where direct targeting of SMAD3 by small molecules can promote mitophagy-mediated endothelial cell rejuvenation 7. SMAD3 function is regulated by ubiquitination-dependent intracellular localization and protein stability 8.