Abstract Body (Do not enter title and authors here): Vein graft failure remains a major challenge after coronary and peripheral bypass surgeries, primarily due to neointimal hyperplasia driven by vascular smooth muscle cell (SMC) phenotypic switching. This maladaptive remodeling arises when vein segments, naturally adapted to low-pressure and low-shear environments, are exposed to arterial circulation, leading to elevated wall tension and disturbed flow. In a murine vein graft model, global knockout of Janus kinase 3 (JAK3) significantly reduced neointimal formation and preserved contractile marker expression in vascular SMCs, suggesting that JAK3 is a key regulator of pathological remodeling. To investigate the mechanism, we performed co-immunoprecipitation and mass spectrometry, which identified the RNA-binding protein TIA1 as a novel substrate of JAK3. TIA1 is a nucleator of stress granules and plays a role in post-transcriptional gene regulation. Using primary SMCs isolated from human saphenous veins collected during coronary artery bypass graft (CABG) surgery, we found that platelet-derived growth factor-BB (PDGF-BB) activates JAK3 and promotes liquid–liquid phase separation (LLPS) of TIA1, resulting in stress granule formation. Fluorescence recovery after photobleaching showed that JAK3 stabilizes TIA1 condensates by reducing their internal mobility. Disruption of these condensates with 1,6-hexanediol restored contractile gene expression in PDGF-BB-treated SMCs, confirming the role of LLPS in regulating SMC phenotype. To explore the downstream effects, RNA immunoprecipitation followed by qPCR demonstrated that TIA1 binds mRNAs encoding contractile proteins including ACTA2, MYH11, TAGLN, and MYOCD. These findings support a model in which LLPS-mediated mRNA sequestration represses translation and promotes a synthetic phenotype. To assess the SMC-specific function of JAK3 in vivo, we generated SMC-specific JAK3 knockout mice, which exhibited reduced neointimal hyperplasia and preserved SMC identity. Analyses of failed CABG human vein grafts revealed increased JAK3 and TIA1 expression and phosphorylation, along with elevated stress granule formation. Finally, molecular docking suggested that JAK3 targets tyrosine residues in the prion-like domain of TIA1 to enhance interactions needed for LLPS. These results define a JAK3–TIA1 signaling axis that governs SMC fate through LLPS-mediated translational repression.