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Berberine ameliorates atherosclerosis by inhibiting the phenotypic transition of vascular smooth muscle cells via suppression of the JAK2/STAT3 signaling pathway

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⚠️ Auto-extracted by Claude on 2026-05-18 — PDF download pending in a local paper archive (status: pending; returns not yet downloaded). Abstract-level extraction only. Specific group n’s, exact % plaque-area reduction, and precise dose values require primary PDF confirmation before being cited quantitatively. CC BY 4.0 — full text available at doi:10.1016/j.ejphar.2025.178234 for verifier access. needs-pdf-fetch

Berberine ameliorates atherosclerosis by inhibiting the phenotypic transition of vascular smooth muscle cells via suppression of the JAK2/STAT3 signaling pathway

Zheng J, Wang T, Zhou Y, Chen Y, Shen X, Jin B, Han X, Hua C, Xie J · Eur J Pharmacol 1007:178234 · 2025 · DOI: 10.1016/j.ejphar.2025.178234 · PMID: 41075918

OA status: CC BY 4.0 (Elsevier hybrid OA). Impact data pending (0 citations recorded as of 2026-05-18 — paper published November 2025, citation accumulation early).

TL;DR

Zheng et al. report a vessel-wall direct-action mechanism for berberine in atherosclerosis: berberine suppresses the contractile-to-synthetic phenotypic transition of vascular smooth muscle cells (VSMCs) by inhibiting STAT3 signaling. In ApoE−/− mice on a high-fat diet, berberine reduced aortic pulse wave velocity and serum lipid levels; in oxLDL-stimulated A7r5 VSMCs, it decreased proliferation, migration, and expression of synthetic-state markers (OPN) while preserving contractile markers (α-SMA). This complements the pre-existing berberine atherosclerosis literature: Kong 2004 established LDLR mRNA stabilization in hepatocytes; the TMAO-gut axis arm (Ma 2022) describes microbiome-mediated effects. Zheng 2025 is the first paper to frame JAK2/STAT3 inhibition in VSMCs as a primary mechanism. needs-replication

Study design

Two-arm experimental design with parallel in-vivo and in-vitro components:

ComponentSystemInductionInterventionKey readouts
In vivoApoE−/− miceHigh-fat diet (HFD) × 12 weeksBerberine (dose: confirm in PDF) × 4 weeksAortic pulse wave velocity, serum lipids, VSMC phenotype markers in plaque
In vitroRat A7r5 VSMC lineox-LDL stimulationBerberine (dose: confirm in PDF)Proliferation, migration, α-SMA / OPN / JAK2 / STAT3 / pJAK2 / pSTAT3 expression

The 12-week HFD induction followed by 4-week intervention is a standard ApoE−/− atherosclerosis protocol; the A7r5 rat VSMC line is a widely used model for VSMC phenotype-switching studies. Specific group n’s and berberine doses are not reported in the abstract and require primary PDF verification. needs-pdf-fetch

In-vivo findings

Berberine treatment in ApoE−/− HFD mice was reported to produce:

  • Reduced aortic pulse wave velocity (aPWV) — measured by ultrasound biomicroscopy; a functional marker of aortic stiffness that integrates both plaque burden and vessel-wall remodeling. needs-pdf-fetch — exact aPWV values (baseline, vehicle, berberine groups) require primary PDF.
  • Decreased serum lipid levels — consistent with established cholesterol-lowering activity of berberine (LDLR mRNA stabilization via ERK; see kong-2004-berberine-ldlr-mechanism). Whether the lipid effect is sufficient to explain the aPWV change, or whether the VSMC-phenotype arm contributes independently, is not resolved from abstract-level data. no-mechanism
  • Reduced phenotypic conversion of VSMCs within plaques — assessed by tissue markers (α-SMA+ contractile retention; OPN / vimentin reduction for synthetic-state suppression). Exact immunostaining quantification requires primary PDF.
DimensionStatus
Pathway (JAK2/STAT3) conserved in humans?yes — JAK2/STAT3 is a canonical mammalian signaling axis; human VSMCs respond to PDGF-BB and inflammatory cytokines via JAK/STAT
Phenotype (VSMC phenotypic switching) conserved in humans?yes — human atherosclerotic plaques contain SMC-derived foam cells and synthetic-state VSMCs; the contractile-to-synthetic transition is established in human coronary artery disease
Replicated in humans?no — no human study of berberine effects on VSMC JAK2/STAT3 or phenotypic switching; clinical trial would require biopsy-based readout

In-vitro findings (A7r5 VSMCs)

ox-LDL-stimulated A7r5 cells treated with berberine showed:

  • Decreased VSMC proliferation and migration — the key functional outputs of the contractile-to-synthetic transition that drive plaque growth and destabilization.
  • Altered marker expression consistent with phenotype-switch suppression:
    • α-SMA (contractile marker) — expression pattern relative to ox-LDL control; direction (preserved vs. restored vs. increased) requires PDF confirmation. needs-pdf-fetch
    • OPN (osteopontin — synthetic/osteogenic marker) — reported as decreased.
    • JAK2 and STAT3 protein levels — reported as decreased.
    • pJAK2 and pSTAT3 (phosphorylation — active-signaling readout) — reported as decreased, consistent with pathway suppression being a proximate mechanism.

The mechanistic claim rests on the phospho-site data: reduced pJAK2 and pSTAT3 with berberine co-treatment establishes that the kinase-activation step is being inhibited, not just downstream transcriptional output. Whether berberine is acting as a direct JAK2 kinase inhibitor (binding the ATP pocket), indirectly via upstream AMPK activation suppressing JAK2 activation, or via another mechanism is not resolved from abstract-level data and is a critical gap. no-mechanism

Mechanistic context: where this fits in the berberine-atherosclerosis story

Berberine has multiple reported mechanisms relevant to cardiovascular aging:

  1. LDLR mRNA stabilization (hepatic) — Kong et al. 2004 via ERK/3’UTR axis; reduces serum LDL-C independently of statins 1.
  2. TMAO-gut microbiome axis — Ma et al. 2022 reported berberine reduces gut-derived TMAO (trimethylamine N-oxide), linking microbiome modulation to reduced proatherogenic signaling. needs-replication — this mechanism requires independent replication.
  3. VSMC JAK2/STAT3 inhibition (vessel-wall direct action) — Zheng et al. 2025 (this paper) 2. First report framing VSMC phenotype switching suppression via JAK2/STAT3 as a mechanism of berberine’s antiatherosclerotic effects.

These three mechanisms are potentially additive: hepatic LDLR upregulation reduces circulating LDL (substrate for atherosclerosis); gut-microbiome-TMAO reduction decreases proatherogenic signaling input; direct vessel-wall VSMC-phenotype stabilization addresses the plaque-growth effector arm. Whether they are fully independent or share upstream nodes (e.g., AMPK could influence both LDLR mRNA stability and JAK2/STAT3 activation) is unresolved. no-mechanism

VSMC phenotypic switching — biological context

VSMC phenotypic switching is a central mechanism in atherosclerosis progression:

  • Contractile state (normal adult VSMCs): expresses α-SMA, SM22α (transgelin), calponin, smoothelin; low proliferation, low ECM secretion.
  • Synthetic state (disease-associated): expresses vimentin, S100A4, OPN, MMP-2/9; high proliferation, high migration, high ECM/collagen secretion, contributes to neointima and unstable plaque.
  • The switch is induced by growth factors (PDGF-BB, EGF), lipid mediators (ox-LDL), and inflammatory cytokines (IL-6, IFN-γ) — many of which signal through JAK/STAT axes.
  • VSMCs in advanced human plaques have been shown by lineage-tracing studies to adopt foam-cell, osteogenic, and fibrocytic identities — making the phenotypic switch a driver of both plaque growth and vulnerability to rupture.

JAK2/STAT3 has been reported as a pro-synthetic signal in VSMCs in the context of injury and inflammation; pharmacological inhibition (including by statins, IL-6R blockade, and now berberine per this paper) is being explored as a stabilization strategy. The JAK-STAT connection links this VSMC mechanism to the broader chronic-inflammation hallmark. needs-replication

Limitations and gaps

  • Group n’s unknown — abstract does not report per-group animal numbers or cell experiment replicates. needs-pdf-fetch
  • Doses unspecified in abstract — in vivo mg/kg and in vitro µM concentrations require PDF verification; dose relevance to human pharmacology cannot be assessed without this. dose-response-unclear
  • No plaque-area quantification reported in abstract — aPWV is a functional/hemodynamic endpoint, not a direct plaque-burden measure; whether aortic sinus cross-sectional plaque area or en face Oil Red O was also measured requires PDF confirmation. needs-pdf-fetch
  • Mechanism not fully resolved — whether berberine inhibits JAK2 directly (kinase binding) or via an upstream effector (AMPK → JAK2 phosphorylation suppression) is not resolved. no-mechanism
  • A7r5 is a rat embryonic aortic VSMC line, not a primary human VSMC or primary mouse VSMC — its phenotypic plasticity profile differs from adult primary VSMCs; findings must be replicated in primary human VSMCs. needs-human-replication
  • No rescue experiment reported in abstract — activating JAK2/STAT3 (e.g., with IL-6 or JAK2 overexpression) to confirm that pathway reactivation reverses berberine’s effects would strengthen the causal claim. needs-replication
  • Human relevance — no human pharmacokinetic–pharmacodynamic data confirms that oral berberine achieves vessel-wall concentrations sufficient to inhibit JAK2/STAT3 in VSMCs in vivo. Berberine’s notoriously low bioavailability (~0.5%) makes this a critical translational gap. needs-human-replication

Cross-references

PageRelationship
berberinePrimary compound studied; this paper adds JAK2/STAT3 VSMC mechanism to its profile
jak-stat-pathwaySignaling pathway suppressed; JAK2/STAT3 is the proposed proximate target
atherosclerosisDisease phenotype studied; in vivo model for outcome validation
chronic-inflammationHallmark addressed; JAK/STAT is a core inflammatory signaling axis
altered-intercellular-communicationVSMC phenotypic switching alters paracrine signaling within the arterial wall
kong-2004-berberine-ldlr-mechanismComplementary mechanism: berberine raises LDLR via ERK/3’UTR (hepatic); distinct from vessel-wall VSMC JAK2/STAT3 effect here

Footnotes

Footnotes

  1. kong-2004-berberine-ldlr-mechanism · n=32 (human arm) · open-label pilot · model: HepG2 cells; hyperlipidemic hamsters; hypercholesterolemic adults · doi:10.1038/nm1135 · LDLR mRNA stabilization via ERK; independent of SREBP-2/statin mechanism ↩

  2. zheng-2025-berberine-vsmc-jak2-stat3 · n=not confirmed (abstract) · in-vivo + in-vitro · model: ApoE−/− HFD mice; A7r5 rat VSMCs/ox-LDL · doi:10.1016/j.ejphar.2025.178234 · PMID: 41075918 · PDF pending (CC BY 4.0) · abstract-level extraction only needs-pdf-fetch ↩

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