Metformin promotes apoptosis of senescent chondrocytes by disrupting the Bcl-xL/Mcl-1–Bak interaction

Abstract

Introduction: The accumulation of senescent chondrocytes (SEC) beyond the body’s tolerance capacity is a key contributor to osteoarthritis (OA) pathogenesis. Metformin (Met), a first-line oral medication for type 2 diabetes, has shown therapeutic potential in various diseases. This study aims to explore the therapeutic effects and underlying mechanisms of Met in OA.

Methods: Cellular senescence was induced in immortalized human chondrocytes using doxorubicin (Dox), confirmed by β-galactosidase staining and western blotting. The effects of Met on SEC viability, mitochondrial membrane potential, and apoptosis were assessed. Protein expression and interactions were analyzed by western blot and live-cell fluorescence resonance energy transfer (FRET) analysis.

Results: Met promoted death of SEC and reduced mitochondrial membrane potential, inducing caspase- and reactive oxygen species (ROS)-dependent apoptosis. Met upregulated Bak and Bim expression, downregulated Mcl-1, and activated Caspase-3, Caspase-8, and Caspase-9, leading to PARP cleavage. FRET analysis revealed that Met disrupted Mcl-1/Bak and Bcl-xL/Bak binding while facilitating Bim-Bak interaction, promoting Bak dimerization.

Discussion: This study provides the first evidence that Met induces apoptosis of SEC by reducing Mcl-1-Bak and Bcl-xL-Bak interactions while enhancing Bim-Bak binding, suggesting a novel therapeutic strategy for OA by targeting senescent chondrocytes through mitochondrial apoptosis pathways.

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BibTeX RIS

BibTeX

@article{feng2026metformin,
  title = {{Metformin promotes apoptosis of senescent chondrocytes by disrupting the Bcl-xL/Mcl-1–Bak interaction}},
  author = {Biying Feng and Longzhou Liu and Yueyang Lin and Guihao Wu},
  journal = {Frontiers in Pharmacology},
  year = {2026},
  month = oct,
  doi = {10.3389/fphar.2026.1944776},
  url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1944776/full},
  note = {CC BY 4.0},
}

RIS

TY  - JOUR
TI  - Metformin promotes apoptosis of senescent chondrocytes by disrupting the Bcl-xL/Mcl-1–Bak interaction
AU  - Biying Feng
AU  - Longzhou Liu
AU  - Yueyang Lin
AU  - Guihao Wu
PY  - 2026
DA  - 2026/10/28
JO  - Frontiers in Pharmacology
DO  - 10.3389/fphar.2026.1944776
UR  - https://www.frontiersin.org/articles/10.3389/fphar.2026.1944776/full
AB  - Introduction: The accumulation of senescent chondrocytes (SEC) beyond the body’s tolerance capacity is a key contributor to osteoarthritis (OA) pathogenesis. Metformin (Met), a first-line oral medication for type 2 diabetes, has shown therapeutic potential in various diseases. This study aims to explore the therapeutic effects and underlying mechanisms of Met in OA.  Methods: Cellular senescence was induced in immortalized human chondrocytes using doxorubicin (Dox), confirmed by β-galactosidase staining and western blotting. The effects of Met on SEC viability, mitochondrial membrane potential, and apoptosis were assessed. Protein expression and interactions were analyzed by western blot and live-cell fluorescence resonance energy transfer (FRET) analysis.  Results: Met promoted death of SEC and reduced mitochondrial membrane potential, inducing caspase- and reactive oxygen species (ROS)-dependent apoptosis. Met upregulated Bak and Bim expression, downregulated Mcl-1, and activated Caspase-3, Caspase-8, and Caspase-9, leading to PARP cleavage. FRET analysis revealed that Met disrupted Mcl-1/Bak and Bcl-xL/Bak binding while facilitating Bim-Bak interaction, promoting Bak dimerization.  Discussion: This study provides the first evidence that Met induces apoptosis of SEC by reducing Mcl-1-Bak and Bcl-xL-Bak interactions while enhancing Bim-Bak binding, suggesting a novel therapeutic strategy for OA by targeting senescent chondrocytes through mitochondrial apoptosis pathways.
SN  - 1663-9812
ER  -

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