Intracranial Arterial Stenosis beyond Atherosclerosis: Insights from RNF213

Intracranial arterial stenosis is a major cause of ischemic stroke worldwide, particularly in the Asian population. Although traditionally regarded as a manifestation of atherosclerotic disease, increasing evidence suggests that non-atherosclerotic arteriopathies also contribute substantially to its pathogenesis. These conditions, including arterial dissection, inflammatory vasculopathies, and moyamoya disease, often share overlapping clinical and imaging features, thus making precise differentiation challenging in routine practice.This phenotypic overlap highlights the heterogeneity of intracranial arterial stenosis and suggests that it may represent a spectrum of vascular disorders, rather than a single disease entity. Recent studies have highlighted the role of genetic susceptibility as a factor underlying this diversity. Among these, RNF213, originally identified as a susceptibility gene for moyamoya disease, has been implicated in a subset of intracranial arterial diseases beyond the classical diagnostic categories. These observations have led to the concept of RNF213-related vasculopathy, which extends beyond intracranial circulation and provides a framework for understanding diverse vascular phenotypes within a broader context. In addition, a two-hit model has been proposed in which genetic susceptibility interacts with environmental and acquired factors to influence the disease onset and progression.This narrative review summarizes the current understanding of intracranial arterial stenosis beyond the conventional atherosclerosis-centered paradigm and discusses emerging concepts integrating vascular heterogeneity, genetic susceptibility, and environmental modifiers with potential implications for disease classification and individualized therapeutic strategies.