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

Figures

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  Figure 3. Activation and regulatory mechanisms of STAT3 signaling. STAT3 signaling can be activated by a wide range of extracellular stimuli, including cytokines (e.g., IL-6, IL-11, and IL-23), growth factors (e.g., PDGF-BB, EGF, and FGF), neurohumoral mediators (e.g., AngII and endothelin-1), as well as physical stressors such as mechanical stretch and ischemia. Upon ligand binding, receptor-associated Janus kinases (JAKs) are activated and induce receptor phosphorylation, creating docking sites for STAT3 recruitment. STAT3 is subsequently phosphorylated at Tyr705, leading to homodimerization through reciprocal SH2 domain interactions and nuclear translocation. In the nucleus, activated STAT3 binds to specific DNA response elements and regulates the transcription of genes involved in cellular proliferation, survival, inflammation, and other biological processes. In addition to canonical Tyr705 phosphorylation, STAT3 activity can be further enhanced by non-canonical post-translational modifications, including Ser727 phosphorylation mediated by MAPKs, mTOR, and PKC, and Lys685 acetylation mediated by p300/CBP. These modifications modulate STAT3 transcriptional activity, protein stability,…

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  Figure 4. STAT3 regulates VSMCs phenotypic switching, proliferation, and migration. Multiple pathological stimuli, including IL-6, VEGF-A, PDGF-BB, Ang II, and high glucose, activate the JAK2/STAT3 signaling pathway. Activated STAT3 promotes the transition of VSMCs from a contractile to a synthetic phenotype through suppression of contractile gene expression and epigenetic remodeling. In addition, STAT3 stimulates VSMCs proliferation by inducing Cyclin D1 and PCNA expression and accelerating G1/S cell-cycle progression. STAT3 also facilitates VSMCs migration through MMP-2/9-mediated ECM degradation and WDR1- and FAK-dependent cytoskeletal remodeling. These coordinated effects contribute to neointimal hyperplasia, atherosclerosis, and vascular remodeling. The figure was created in BioRender.

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  Figure 6. Mechanisms by which STAT3 regulates ECM homeostasis in VSMCs. Various upstream stimuli, including AngII, homocysteine (Hcy), and inflammatory cytokines, activate STAT3 signaling in VSMCs. The transcriptional activity of STAT3 is cooperatively regulated by Lys685 acetylation (AcK685) and Tyr705 phosphorylation (pY705). WWP2 enhances STAT3 activation by suppressing SIRT1-mediated deacetylation, whereas Septin4 exerts an opposing effect by facilitating the interaction between SIRT1 and STAT3. On the ECM synthesis side, activated STAT3 cooperates with JunB to promote the transcription of ECM-related genes, including COL1A2, COL3A1, FN1, and ELN, thereby enhancing ECM production. On the ECM degradation side, STAT3 regulates the expression of MMP-2 and MMP-9 and their endogenous inhibitor TIMP1. Because the stimulatory effect on TIMP1 predominates, the overall consequence is reduced ECM degradation. In addition, BAG3 modulates ECM turnover by differentially regulating STAT3 Tyr705 and Ser727 phosphorylation and subsequently affecting MMP-2 expression. Through coordinated regulation of ECM synthesis and degradation, STAT3 promotes net ECM accumulation, drives vascular remodeling, and…

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  Figure 1. Schematic overview of the STAT3 signaling axis in VSMCs functional remodeling and therapeutic targeting. An Overview of STAT3: Structural domains of STAT3 (NTD to TAD) and its post-translational activation (phosphorylation and acetylation), strictly regulated by upstream kinases (JAK2) and negative feedback loops (SOCS, PIAS, and PTPs). STAT3 and VSMCs Functions: Pathological activation of STAT3 driving VSMCs phenotypic switching from the contractile to synthetic phenotype, subsequently orchestrating aberrant proliferation, migration, ECM remodeling, apoptosis, and pyroptosis. STAT3 Signaling Axis and Cross-talk: Molecular networks intersecting with STAT3, including the classical IL-6/JAK2 and PDGF-BB/Src cascades, SIRT1-mediated deacetylation, and reciprocal cross-talk with parallel pathways (PI3K-Akt-mTOR, Wnt/β-catenin, and TGF-β1/Stat3-FoxO). STAT3 Inhibitors: Stratification of therapeutic strategies counteracting hyperactive STAT3, classified into direct targeting (SH2 domain dimerization inhibitors), indirect targeting (upstream kinase inhibitors), and multi-target bioactive natural products. Note: Solid arrows indicate activation or promotion; T-shaped bars represent…

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  Figure 2. Structural organization and functional domains of STAT3. STAT3 is a modular transcription factor composed of six conserved domains arranged from the N-terminus to the C-terminus: the NTD, CCD, DBD, LD, SH2D, and TAD. The NTD facilitates receptor recruitment and contributes to STAT3 phosphorylation, dimerization, and nuclear translocation. The CCD mediates protein–protein interactions and may participate in DNA-binding specificity. The DBD recognizes specific DNA elements within target gene promoters, whereas the LD maintains the structural coordination between the DBD and SH2D. The SH2D is essential for phosphotyrosine recognition and STAT3 homodimer formation. The TAD contains the critical phosphorylation sites Tyr705 and Ser727 and recruits transcriptional co-activators, such as p300/CBP, to enhance transcriptional activation of downstream target genes. The figure was created in BioRender.

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  Figure 5. Molecular mechanisms by which STAT3 regulates apoptosis and pyroptosis in VSMCs. STAT3 plays a dual role in regulating the fate of VSMCs, contributing to vascular remodeling and inflammatory vascular diseases by suppressing apoptosis while promoting pyroptosis. Upon stimulation by cytokines or growth factors, activation of the JAK/STAT3 signaling pathway induces STAT3 phosphorylation, followed by its nuclear translocation and transcriptional activation of downstream target genes. In the anti-apoptotic pathway, STAT3 directly promotes the transcription of anti-apoptotic genes, including Bcl-2, Bcl-xL, Mcl-1, and Survivin, thereby suppressing mitochondrial apoptotic signaling, reducing cytochrome c release and subsequent Caspase-9/Caspase-3 activation, and ultimately enhancing VSMCs survival and neointimal formation following vascular injury. In contrast, the dominant-negative STAT3 mutant (Y705F) inhibits STAT3-dependent transcriptional activity, leading to increased VSMCs apoptosis and attenuation of pathological neointimal hyperplasia. In the pyroptotic pathway, STAT3 promotes inflammatory cell death through two major mechanisms. First, STAT3 interacts with NLRP3 and facilitates…

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  Figure 7. STAT3-mediated metabolic reprogramming in VSMCs. STAT3 functions as a central regulator of metabolic reprogramming in VSMCs by integrating multiple upstream stimuli, including Ang II, Hcy, and inflammatory cytokines. Activated STAT3 promotes a Warburg-like glycolytic phenotype through upregulation of key glycolytic enzymes, including HK2, PKM2, and LDHA, thereby enhancing glycolytic flux and supporting the energy demands of VSMCs phenotypic switching, proliferation, and migration. STAT3 also regulates mitochondrial homeostasis and glutamine metabolism by modulating mitochondrial function and GLS-dependent α-KG production, which replenishes the TCA cycle and supports biosynthetic processes. In addition, STAT3 promotes ox-LDL uptake, lipid accumulation, and foam cell formation, contributing to atherosclerotic plaque progression. The transcriptional activity of STAT3 is further modulated by WWP2, Septin4, BAG3, and pharmacological inhibitors such as quercetin. Collectively, STAT3 orchestrates multiple metabolic pathways that drive VSMCs dysfunction and vascular disease progression. The figure was created in BioRender.