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<p>Anti-angiogenic agents targeting vascular endothelial growth factor receptors, such as regorafenib, are widely used across multiple malignancies, yet their clinical benefit is frequently constrained by cardiovascular toxicity, particularly hypertension, for which the mechanisms remain incompletely defined. In this study, a drug-induced hypertension model was established in mice by daily oral administration of regorafenib at 200&#xa0;mg/kg for 6&#xa0;weeks. The results showed that regorafenib administration induced a robust increase in blood pressure accompanied by arterial wall remodeling in mouse model. Single-cell transcriptomic profiling of mouse aortas pinpointed VSMCs as the principal responsive population, and subsequent mechanistic studies demonstrated that regorafenib promotes a contractile-to-synthetic phenotypic transformation in VSMCs and ultimately triggers mitochondrial injury and apoptosis. We further identified high mobility group box 1 (HMGB1) as a critical mediator of these effects: regorafenib markedly increased HMGB1 in VSMCs, HMGB1 regulated the transcriptional program governing VSMC identity by modulating the expression of contractile and lineage-defining genes, including <i>ACTA2</i>, <i>TAGLN</i>, and <i>SRF</i>. Therapeutically, VSMC-specific <i>Hmgb1</i> deletion in mouse model or combined administration of 20&#xa0;mg/kg HMGB1 pharmacological inhibitor tanshinone IIA normalized blood pressure and mitigated vascular remodeling. Collectively, our findings define VSMCs as a key cellular target of regorafenib-induced vascular toxicity and reveal an HMGB1-centered transcriptional mechanism that controls ACTA2/TAGLN/SRF expression to drive VSMC phenotypic transformation, highlighting HMGB1 inhibition (e.g., tanshinone IIA) as a potential strategy to improve the cardiovascular safety of anti-angiogenic therapy.</p> Graphical Abstract <p>1. Regorafenib upregulates HMGB1 to induce VSMC phenotypic transformation and apoptosis.</p> <p>2. HMGB1 suppresses SRF signaling and impairs VSMC contractile phenotype.</p> <p>3. VSMC injury causes vascular remodeling and increased peripheral resistance.</p> <p>4. Tanshinone IIA targets HMGB1 to alleviate regorafenib-induced hypertension.</p> <p></p>

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HMGB1 mediates regorafenib-induced hypertension by regulating vascular smooth muscle cell phenotypic transformation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月29日

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  • Jian Chen,
  • Ning Liu,
  • Fuyuan Jian,
  • Bo Xu,
  • Huangxi Fu,
  • Ruoyu Wang,
  • Jingjing Jiang,
  • Ruoyu He,
  • Hao Yan,
  • Peihua Luo,
  • Bo Yang,
  • Qiaojun He,
  • Peng Lu,
  • Zhifei Xu

摘要

Anti-angiogenic agents targeting vascular endothelial growth factor receptors, such as regorafenib, are widely used across multiple malignancies, yet their clinical benefit is frequently constrained by cardiovascular toxicity, particularly hypertension, for which the mechanisms remain incompletely defined. In this study, a drug-induced hypertension model was established in mice by daily oral administration of regorafenib at 200 mg/kg for 6 weeks. The results showed that regorafenib administration induced a robust increase in blood pressure accompanied by arterial wall remodeling in mouse model. Single-cell transcriptomic profiling of mouse aortas pinpointed VSMCs as the principal responsive population, and subsequent mechanistic studies demonstrated that regorafenib promotes a contractile-to-synthetic phenotypic transformation in VSMCs and ultimately triggers mitochondrial injury and apoptosis. We further identified high mobility group box 1 (HMGB1) as a critical mediator of these effects: regorafenib markedly increased HMGB1 in VSMCs, HMGB1 regulated the transcriptional program governing VSMC identity by modulating the expression of contractile and lineage-defining genes, including ACTA2, TAGLN, and SRF. Therapeutically, VSMC-specific Hmgb1 deletion in mouse model or combined administration of 20 mg/kg HMGB1 pharmacological inhibitor tanshinone IIA normalized blood pressure and mitigated vascular remodeling. Collectively, our findings define VSMCs as a key cellular target of regorafenib-induced vascular toxicity and reveal an HMGB1-centered transcriptional mechanism that controls ACTA2/TAGLN/SRF expression to drive VSMC phenotypic transformation, highlighting HMGB1 inhibition (e.g., tanshinone IIA) as a potential strategy to improve the cardiovascular safety of anti-angiogenic therapy.

Graphical Abstract

1. Regorafenib upregulates HMGB1 to induce VSMC phenotypic transformation and apoptosis.

2. HMGB1 suppresses SRF signaling and impairs VSMC contractile phenotype.

3. VSMC injury causes vascular remodeling and increased peripheral resistance.

4. Tanshinone IIA targets HMGB1 to alleviate regorafenib-induced hypertension.