Molecular Mechanisms and Therapeutic Targeting of the STAT3 Signaling Axis in Vascular Smooth Muscle Cell Phenotypic Switching and Vascular Remodeling

Vascular smooth muscle cells (VSMCs) exhibit remarkable phenotypic plasticity, dynamically transitioning from a quiescent contractile state to a dedifferentiated synthetic phenotype that constitutes the fundamental cytological driver of pathological vascular remodeling in cardiovascular diseases (CVDs) including atherosclerosis, vascular restenosis, aortic dissection (AD), and vascular calcification (VC). Signal transducer and activator of transcription 3 (STAT3) operates as a master transcriptional and functional convergence node, integrating diverse upstream biochemical stimuli, neurohumoral factors, and biomechanical stressors to govern downstream gene regulatory networks. Aberrant STAT3 activation orchestrates VSMC phenotypic modulation, excessive proliferation, directional migration, programmed cell death involving apoptosis resistance and pyroptosis initiation, extracellular matrix (ECM) reorganization, and glycolytic metabolic reprogramming via canonical nuclear transcription and non-canonical subcellular actions. Here, we systematically delineate the modular structural organization, post-translational modifications, and negative regulatory feedback mechanisms of STAT3 in shaping VSMC functionality. Furthermore, we synthesize recent advances in pharmacological interventions by comprehensively categorizing therapeutic modalities into direct structural-domain inhibitors, upstream kinase-targeted indirect agents, bioactive natural products, and emerging clinical-stage translational candidates. Finally, we critically address translational hurdles regarding on-target systemic toxicities, and highlight site-specific vascular delivery systems alongside localized drug-eluting vascular devices to advance precision STAT3-targeted cardiovascular therapeutics.