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Gastrodin alleviates cardiomyocyte senescence by regulating autophagy through the AMPK/mTOR/4EBP1 pathway

Mingyue Yao1, Simin Zhang1, Yan Wu1

  • 1The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, China.

Frontiers in Pharmacology
|July 1, 2026
PubMed
Abstract

Insights

Gastrodin (Gas) protects heart cells from doxorubicin (Dox)-induced aging and death by activating AMPK/mTOR/4EBP1 signaling and improving autophagy. This study reveals Gas as a potential therapeutic agent for preventing Dox-induced cardiotoxicity.

Area of Science:

  • Cardiovascular Biology
  • Cellular Senescence
  • Molecular Mechanisms

Background:

  • Doxorubicin (Dox) is a potent chemotherapy agent with known cardiotoxic side effects.
  • Dox-induced cardiomyocyte senescence and apoptosis contribute to heart failure.
  • Targeting cellular signaling pathways and autophagy presents a potential therapeutic strategy.

Purpose of the Study:

  • To investigate the protective effects of Gastrodin (Gas) against doxorubicin (Dox)-induced cardiomyocyte senescence and apoptosis.
  • To elucidate the role of the AMPK/mTOR/4EBP1 signaling pathway and autophagy in mediating Gas's protective effects.

Main Methods:

  • Establishment of a Dox-induced senescence model in H9c2 cardiomyocytes.
  • Intervention with varying concentrations of Gastrodin (Gas).
  • Assessment of senescence phenotypes (SA-β-gal staining, P16, P21, P53 expression).
  • Analysis of apoptosis using Annexin V/PI flow cytometry.
  • Evaluation of autophagy markers (LC3-II/I, Beclin-1, p62) and AMPK/mTOR/4EBP1 pathway proteins via Western blotting and immunofluorescence.
  • Utilisation of autophagy inhibitor (3-MA) and AMPK inhibitor (Compound C).

Main Results:

  • Gastrodin (Gas) dose-dependently reduced SA-β-gal-positive cells and downregulated senescence markers (P16, P21, P53, γ-H2AX).
  • Gas significantly inhibited cardiomyocyte apoptosis.
  • Gas treatment improved autophagy markers (increased LC3, Beclin-1; decreased p62), an effect partially reversed by 3-MA.
  • Gas activated the AMPK/mTOR/4EBP1 pathway by increasing p-AMPK/AMPK and decreasing p-mTOR/mTOR and p-4EBP1/4EBP1.
  • AMPK inhibition abolished Gas's protective effects on autophagy, senescence, and apoptosis.

Conclusions:

  • Gastrodin (Gas) effectively alleviates doxorubicin (Dox)-induced cardiomyocyte senescence and apoptosis.
  • The protective mechanism involves the regulation of the AMPK/mTOR/4EBP1 signaling pathway.
  • Gastrodin (Gas) improves autophagy-related processes, contributing to its cardioprotective effects.
Keywords:
AMPK/mTOR/4EBP1 pathwayautophagycardiomyocytesgastrodin (GAS)senescence

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