TGFBR1 is a transmembrane serine/threonine kinase that functions as the type I receptor for TGF-β cytokines (TGFB1, TGFB2, TGFB3) 1. It forms a heterotetrameric receptor complex with TGFBR2, which activates canonical SMAD-dependent signaling through phosphorylation of SMAD2, leading to translocation of SMAD2-SMAD4 complexes to the nucleus to modulate gene transcription 1. TGFBR1 also engages non-canonical pathways, including TRAF6-mediated apoptosis and epithelial-to-mesenchymal transition through PARD6A phosphorylation 1. TGFBR1 mutations cause Loeys-Dietz syndrome, an autosomal dominant aortic aneurysm disorder characterized by arterial tortuosity, hypertelorism, and bifid uvula/cleft palate, with aggressive vascular disease and early mortality (mean age 26 years) 2. Paradoxically, patient tissues show increased TGF-β signaling despite loss-of-function mutations 34, suggesting compensatory mechanisms. TGFBR1 mutations also perturb craniofacial, neurocognitive and skeletal development 3. TGFBR1 haploinsufficiency associates with cancer susceptibility; the *6A polymorphism (9-bp deletion in exon 1) reduces TGF-β signaling capability and increases colorectal and breast cancer risk 56. Recent evidence shows NPC1 stabilizes TGFBR1 through preventing SMAD7/SMURF-mediated ubiquitylation, promoting hepatocellular carcinoma progression 7. Conversely, renal fibrosis studies demonstrate that Nrp1/TGFBR1 dual deletion better ameliorates injury than single knockouts 8.