The extracellular matrix glycoprotein fibrillin-1 in health and disease

**Background:** Fibrillin-1 (FBN1) is a large, cysteine-rich, calcium-binding extracellular matrix (ECM) glycoprotein encoded by the *FBN1* gene on chromosome 15q15-21.1. It serves as the primary structural component of 10–12 nm microfibrils, providing force-bearing mechanical support in elastic and nonelastic connective tissues. FBN1 is expressed during embryonic development and in adult tissues, with highest mRNA levels in cultured fibroblasts, subcutaneous adipose tissue, aorta, coronary artery, esophagus, tibial nerve, and ovary. Beyond its structural role, FBN1 interacts with numerous microfibril-associated proteins, growth factors (e.g., TGF-β, BMPs), and cell surface receptors, thereby mediating cell survival, proliferation, migration, and differentiation. Dysregulation of FBN1 is involved in the pathogenesis of many human diseases, including Marfan syndrome (MFS), cancers, cardiovascular disorders, and kidney diseases. Paradoxically, both depletion and overexpression of FBN1 upregulate TGF-β bioavailability and signaling via distinct mechanisms.

**Methods:** This is a narrative review summarizing the structure, expression, and function of FBN1 in health and disease. The authors synthesized findings from published literature, including studies on FBN1 domain structure, expression patterns (using GTEx portal data and immunohistochemistry), microfibril assembly, TGF-β modulation, genetic mutations, and roles in tumorigenesis, kidney diseases, and other organ systems. They also referenced their own proteomic profiling of ECM proteins in fibrotic kidney, which showed significant upregulation of FBN1 in decellularized kidney tissue scaffolds from chronic kidney disease (CKD) models.

**Key Results:** FBN1 is a 350 kDa protein with 2871 amino acids, containing 47 EGF-like domains (43 calcium-binding), 7 TB domains, 2 hybrid domains, and a proline-rich region. The TB4 domain contains an RGD motif that binds integrins α5β1, α5β6, αvβ3, αvβ6, and α8β1. Mutations in the TB5-cbEGF18 region cause neonatal Marfan syndrome. FBN1 null mice die perinatally from aortic aneurysm rupture. In MFS, over 3000 FBN1 mutations are known; point mutations account for 66.3%, deletions 16.1%, splice site mutations 10.9%, insertions 5.4%, and duplications 0.2%. Missense mutations (82.9% of point mutations) often involve cysteine substitutions in cbEGF domains (73.1%). FBN1 is upregulated in gastric cancer, colorectal cancer, osteosarcoma, papillary thyroid carcinoma, renal cell carcinoma, and ovarian cancer, where it promotes proliferation, invasion, and chemoresistance via pathways including TGF-β1/PI3K/Akt, VEGFR2/STAT2, and miR-133b/miR-140-5p. In CKD, FBN1 is induced in tubular epithelial cells and accumulates in the ECM, forming a fibrogenic niche that triggers endothelial cell apoptosis via integrin αvβ6/TGF-β1/Smad3 signaling, contributing to vascular rarefaction. Serum FBN1 levels correlate negatively with eGFR and positively with serum creatinine, BUN, and cystatin C. In MFS mouse models (Fbn1^C1039G/+^), TGF-β antagonism with neutralizing antibody or losartan normalizes MMP-2 and MMP-9 expression and prevents thoracic aortic aneurysm, though clinical trials in humans have shown mixed results. FBN1 also regulates ERK1/2 signaling, VEGFR2/FAK/AKT, and p53 pathways.

**Clinical Implications:** FBN1 is a critical ECM protein whose dysregulation underlies a spectrum of diseases. In MFS, understanding the dominant-negative vs. haploinsufficiency mechanisms guides genotype-phenotype correlations and potential therapies (e.g., losartan, TGF-β antagonists). FBN1 upregulation in cancers suggests its utility as a biomarker and therapeutic target; for example, FBN1 methylation in stool samples is a non-invasive screening tool for colorectal cancer. In CKD, FBN1 depletion improves renal fibrosis and vascular rarefaction in mouse models, indicating that targeting FBN1 or its downstream integrin/TGF-β signaling could be a novel strategy to slow CKD progression. The paradoxical activation of TGF-β by both FBN1 loss and gain highlights the context-dependent nature of FBN1 actions, necessitating further research to develop precise interventions for FBN1-related diseases.