Vascular restenosis, a pathological recurrence of lumen narrowing following interventions, remains a major limitation to the long-term success of vascular procedures. Its development is centrally driven by neointimal hyperplasia, a process orchestrated by endothelial injury, phenotypic switching of vascular smooth muscle cells (VSMCs) from a contractile to a synthetic state, and a coordinated inflammatory response. Despite advancements, the molecular mechanisms are not fully elucidated, and specific, effective pharmacotherapies are still lacking. This review systematically delineates the pathophysiology, focusing on these three core elements, and provides a comprehensive landscape of the complex signaling networks and molecular targets. We extensively cover protein-based regulators—including pro-proliferative factors (e.g., LSD1, FGF10), protective mediators (e.g., CGRP, A20), dual-action molecules with isoform-specific or context-dependent effects (e.g., KLFs, HDACs), endothelial repair targets (e.g., VEGF), and molecules that coordinately target both VSMCs and endothelial cells (ECs) (e.g., PERK, METTL3). We place significant focus on non-coding RNAs, particularly microRNAs (miRNAs) like miR-221/222, which fine-tune multiple targets in both VSMCs and ECs, offering unique precision. We critically evaluate the therapeutic significance and clinical translation potential, while addressing formidable challenges: functional duality within protein families (e.g., KLFs, HDACs), difficulties in cell-specific delivery and stability for miRNA therapies, and a narrow therapeutic window. Additionally, we highlight the emerging role of the vascular adventitia as a key source of regulatory signals (e.g., FGF10). By integrating insights from molecular mechanisms to therapeutic interventions, this work serves as a valuable reference for identifying novel strategies to combat neointima formation and vascular restenosis.

Ginkgolic acid (GA) exhibits various biological activities, but its role in vascular restenosis remains unreported. GA (13:0) is a relatively abundant natural congener. This study aims to investigate and clarify the effects and mechanisms of GA (13:0) on vascular smooth muscle cell (VSMC) proliferation and migration in vitro, as well as on balloon injury-induced vascular restenosis in rats. The results showed that GA (13:0) significantly inhibited VSMC proliferation, migration, and intimal thickening both in vitro and in vivo. Moreover, GA (13:0) reduced the expression of cyclin D1, cyclin E1, CDK2, and CDK4, as well as cyclin D1-CDK4 and cyclin E1-CDK2 binding, leading to G0/G1 arrest. Additionally, GA (13:0) suppressed vimentin expression and actin cytoskeleton polymerization and altered F-actin morphology. Comparative proteomics identified tectonic family member 1 (TCTN1) as a potential molecular target of GA (13:0). GA (13:0) reduced TCTN1 expression both in vitro and in vivo. Crucially, TCTN1 overexpression notably reversed the inhibitory effects of GA (13:0) on VSMC proliferation, migration, intimal thickening, expression and binding of cell cycle-related proteins, and vimentin expression. Concurrently, TCTN1 overexpression also reversed GA (13:0)-induced F-actin depolymerization and rearrangement and G0/G1 arrest. GA (13:0) significantly inhibited TCTN1 co-localization with vimentin and actin in vitro and in vivo. Furthermore, we found that CCCTC binding factor (CTCF) binds to the 162–176 site of the TCTN1 promoter to regulate TCTN1 transcription, and CTCF knockout significantly down-regulated TCTN1 protein levels. This study reveals that GA (13:0) inhibits TCTN1 transcription and expression, hindering G1/S transition, vimentin expression, and F-actin rearrangement, thereby suppressing vascular restenosis.