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A Combined SIRT5 Activation and SIRT3 Inhibition Prevents Breast Cancer Spheroids Growth by Reducing HIF-1α and

Federica Barreca1, Michele Aventaggiato2, Mario Cristina3

  • 1Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy.

Pharmaceuticals (Basel, Switzerland)
|January 28, 2026
PubMed

Insights

Simultaneously inhibiting SIRT3 and activating SIRT5 reduced triple-negative breast cancer spheroid size by targeting glutamine metabolism and increasing mitochondrial ROS. This combined approach offers a novel anti-tumor strategy.

Area of Science:

  • Cancer Biology
  • Metabolic Reprogramming
  • Mitochondrial Function

Background:

  • Metabolic reprogramming is a hallmark of cancer.
  • Mitochondrial sirtuins SIRT3 and SIRT5 play distinct roles in glutamine metabolism, impacting cancer progression.
  • Targeting glutamine metabolism via SIRT3 and SIRT5 is a potential anti-cancer strategy.

Purpose of the Study:

  • To investigate the anti-tumoral effects of simultaneously modulating SIRT3 and SIRT5 in triple-negative breast cancer.
  • To evaluate the impact of combined SIRT3 inhibition and SIRT5 activation on cancer cell metabolism, hypoxia, autophagy, and mitophagy.

Main Methods:

  • Utilized triple-negative breast cancer spheroids (wild-type and GLS1-silenced).
  • Treated spheroids with a selective SIRT3 inhibitor (3-TYP) and a selective SIRT5 activator (MC3138), alone and in combination.
  • Assessed effects on hypoxia, autophagy, mitophagy markers, mitochondrial morphology (TEM), and mitochondrial ROS production.

Main Results:

  • Combined 3-TYP and MC3138 treatment reduced spheroid size.
  • Treatment affected key regulators including HIF-1α, c-Myc, and SLC1A5, and altered autophagy/mitophagy markers (LC3II, BNIP3).
  • Observed significant changes in mitochondrial morphology and an increase in mitochondrial ROS (mtROS).

Conclusions:

  • Combined inhibition of SIRT3 and activation of SIRT5 represents a novel anti-tumoral strategy.
  • This approach effectively reduces cancer spheroid size by inhibiting hypoxic response.
  • The treatment leads to altered autophagic/mitophagic processes and toxic accumulation of mtROS.
Keywords:
autophagyglutamine metabolismmitophagysirtuinstriple negative breast cancer

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