SMAD3 is a receptor-regulated SMAD protein that functions as a key intracellular signal transducer in TGF-β and activin signaling pathways. Upon activation by type 1 receptor kinases, SMAD3 forms complexes with SMAD4 and other transcription factors to regulate gene expression at TRE and AP-1/SMAD binding sites. Beyond canonical TGF-β signaling, SMAD3 can be activated by activin A in macrophages independent of TGF-β, where it controls anti-inflammatory responses through mitochondrial ATP metabolism 1. SMAD3 regulates multiple physiological processes including chondrogenesis, osteogenesis, and wound healing, with inhibitory effects on bone fracture repair and keratinocyte migration. In disease contexts, SMAD3 hyperactivation drives pathological fibrosis and cancer progression. EZH2-mediated methylation of SMAD3 at K53/K333 promotes its phosphorylation and activation, correlating with poor survival in breast cancer and facilitating tumor metastasis 2. Creatine and dietary factors enhance colorectal and breast cancer metastasis by activating SMAD2/3 signaling 3. In renal fibrosis and endometriosis, the TGF-β1/SMAD3 pathway drives pathological fibrogenesis and myofibroblast activation 4; pharmacological SMAD3 inhibition attenuates disease progression. SMAD3 also regulates ovarian cancer metastasis by promoting cancer-associated adipocyte formation in pre-metastatic niches 5. Clinically, SMAD3 inhibition and targeted antisense oligonucleotides blocking SMAD3-dependent mechanisms show therapeutic promise in fibrotic and malignant diseases.