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Peer-reviewedCC BY 4.0Cells

Tirzepatide Attenuates Pulmonary Vascular Remodeling in Pulmonary Arterial Hypertension: Association with the SIRT1/H4K12la/c-Jun Axis

  • Sutong Zhan1
  • Yong Deng2
  • Peilin Chen1
  • Tangfeng Lv1
  • Yong Song1
  • Jiaxin Liu3
  • Chuiyu Kong2
  1. 1Department of Respiratory and Critical Care Medicine, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing 210000, China
  2. 2Department of Cardiac Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210000, China
  3. 3Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210000, China
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Abstract

Metabolic reprogramming and the phenotypic switching of pulmonary arterial smooth muscle cells (PASMCs) are critical pathological features of pulmonary arterial hypertension (PAH). Here, we demonstrated that Tirzepatide (TZP) can significantly ameliorate echocardiographic indicators of pulmonary vascular load and attenuate distal pulmonary vascular remodeling by suppressing PASMC phenotypic switching. Metabolomics and cellular metabolic flux analyses revealed that TZP corrected the Warburg effect, thereby attenuating intracellular lactate accumulation, which we identified as a driver that promotes the synthetic phenotype in PASMCs and exacerbates PAH. Mechanistically, the protective effects of TZP were strongly associated with the activation of the AMPK/SIRT1 signaling pathway, which mediated a significant reduction in histone H4 lysine 12 lactylation (H4K12la). This epigenetic reduction suppressed the transcription of the proto-oncogene Jun and its downstream pathways, which promote PASMC phenotypic switching and PAH deterioration. Thus, we propose a working model wherein TZP attenuates PAH progression by modulating pathological metabolism and reducing c-Jun transcription via the AMPK/SIRT1/H4K12la axis. These findings provide preliminary translational implications for targeting metabolic-epigenetic crosstalk and offer a preclinical rationale for exploring TZP as a protective pharmacological strategy in PAH.

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Cite

BibTeXRIS
BibTeX
@article{zhan2026tirzepatide,
  title = {{Tirzepatide Attenuates Pulmonary Vascular Remodeling in Pulmonary Arterial Hypertension: Association with the SIRT1/H4K12la/c-Jun Axis}},
  author = {Sutong Zhan and Yong Deng and Peilin Chen and Tangfeng Lv and Yong Song and Jiaxin Liu and Chuiyu Kong},
  journal = {Cells},
  year = {2026},
  month = oct,
  doi = {10.3390/cells15201900},
  url = {https://www.mdpi.com/2073-4409/15/20/1900},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Tirzepatide Attenuates Pulmonary Vascular Remodeling in Pulmonary Arterial Hypertension: Association with the SIRT1/H4K12la/c-Jun Axis
AU  - Sutong Zhan
AU  - Yong Deng
AU  - Peilin Chen
AU  - Tangfeng Lv
AU  - Yong Song
AU  - Jiaxin Liu
AU  - Chuiyu Kong
PY  - 2026
DA  - 2026/10/19
JO  - Cells
DO  - 10.3390/cells15201900
UR  - https://www.mdpi.com/2073-4409/15/20/1900
AB  - Metabolic reprogramming and the phenotypic switching of pulmonary arterial smooth muscle cells (PASMCs) are critical pathological features of pulmonary arterial hypertension (PAH). Here, we demonstrated that Tirzepatide (TZP) can significantly ameliorate echocardiographic indicators of pulmonary vascular load and attenuate distal pulmonary vascular remodeling by suppressing PASMC phenotypic switching. Metabolomics and cellular metabolic flux analyses revealed that TZP corrected the Warburg effect, thereby attenuating intracellular lactate accumulation, which we identified as a driver that promotes the synthetic phenotype in PASMCs and exacerbates PAH. Mechanistically, the protective effects of TZP were strongly associated with the activation of the AMPK/SIRT1 signaling pathway, which mediated a significant reduction in histone H4 lysine 12 lactylation (H4K12la). This epigenetic reduction suppressed the transcription of the proto-oncogene Jun and its downstream pathways, which promote PASMC phenotypic switching and PAH deterioration. Thus, we propose a working model wherein TZP attenuates PAH progression by modulating pathological metabolism and reducing c-Jun transcription via the AMPK/SIRT1/H4K12la axis. These findings provide preliminary translational implications for targeting metabolic-epigenetic crosstalk and offer a preclinical rationale for exploring TZP as a protective pharmacological strategy in PAH.
SN  - 2073-4409
ER  -