RNF213 in Panvascular Disease: A Molecular Hub Linking Genetic Susceptibility to Systemic Vasculopathy

Panvascular diseases, characterized by systemic vascular dysfunction across multiple organ systems, represent a complex interplay of genetic susceptibility and environmental triggers. Ring Finger Protein 213 (RNF213), initially identified as the principal susceptibility gene for moyamoya disease (MMD), has emerged as a central regulator of panvascular pathophysiology. This review synthesizes current evidence elucidating RNF213′s multifaceted roles in vascular homeostasis, spanning its functions as an E3 ubiquitin ligase, mechanosensor, and immune modulator. The “second-hit” hypothesis posits that RNF213 mutations establish a genetic predisposition, while secondary insults—such as infection, hypoxia, or hemodynamic stress—precipitate pathological manifestations. Mechanistically, RNF213 orchestrates critical processes including endothelial integrity, angiogenesis, and inflammatory responses through pathways such as HIF-1α/VEGF, NF-κB, and Wnt signaling. Its dysfunction disrupts vascular remodeling, promotes aberrant smooth muscle proliferation, and exacerbates hypoxia-inflammation cycles, contributing to diverse pathologies ranging from intracranial aneurysms and arterial dissections to pulmonary hypertension and coronary artery disease. Emerging insights into RNF213′s interactions with gut microbiota, lipid metabolism, and epigenetic regulators further underscore its systemic influence. Despite advancements, unresolved questions persist regarding the context-dependent duality of RNF213 variants and organ-specific regulatory mechanisms. This review highlights the imperative for integrated approaches combining genetic, molecular, and environmental perspectives to unravel RNF213′s panvascular roles. We also outline unresolved questions regarding context-dependent effects of RNF213 variants and organ-specific regulatory mechanisms, and discuss potential avenues for future research integrating genetic, molecular, and environmental perspectives to advance understanding of RNF213′s panvascular roles.