FBLN5 is an extracellular matrix protein essential for elastic fiber assembly and vascular development. It stabilizes elastin polymers and organizes elastic fibers in skin, lung, and vasculature by promoting interactions between microfibrils and elastin, and acts as an adapter linking fibrillin-1 and elastin. The protein also promotes endothelial cell adhesion through integrin binding via its RGD motif. Pathogenic variants in FBLN5 cause autosomal dominant and recessive cutis laxa, characterized by skin laxity and elastic fiber fragmentation 1. Loss-of-function effects are severe: Fbln5-knockout mice at 20 weeks exhibit arterial stiffness equivalent to 100-week wild-type mice, indicating accelerated vascular aging 2. Post-translational modification by PAD2-mediated citrullination protects FBLN5 from degradation and enhances elastogenesis, explaining how elastin deposition is developmentally regulated 3. Beyond structural roles, FBLN5 has emerged as a tumor suppressor. In non-small-cell lung cancer, elevated stromal FBLN5 paradoxically promotes radioresistance by binding integrin αVβ5, activating the Src-STAT3 pathway, and impairing ferroptosis 4. Conversely, FBLN5 overexpression selectively kills MYC-transformed cells while sparing normal cells, identifying it as a synthetic lethal partner of MYC 5. These opposing contexts suggest FBLN5 function is highly context-dependent, with potential therapeutic implications in both elastic fiber disorders and cancer therapy.