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FTO-Mediated Mitigation of Ferroptosis Occurs in an ACSL4-Dependent Manner in Diabetic Cardiomyopathy
Xin-Xin Chen1, Yan Gu2, Zhe Yin1
1Department of Burn Surgery, The First Hospital of Jilin University, Jilin University, Changchun, 130021, China.
Abstract:
Considering the global prevalence of diabetes, diabetic cardiomyopathy (DCM), as a significant diabetes complication, remains a major human challenge; while previous studies have identified ferroptosis as an important underlying mechanism, the unclear regulatory mechanisms hamper the development of therapy for DCM. In this study, we reveal that the expression of the fat mass and obesity-associated protein (FTO) is downregulated in DCM. Overexpression of FTO was found to enhance cardiac function by inhibiting ferroptosis. Mechanistically, acyl - CoA synthetase long - chain family 4 (ACSL4), a key positive mediator of ferroptosis, was identified as a direct target of FTO. The ameliorative effect of FTO was contingent upon the inhibition of ACSL4, and FTO-mediated mitigation of ferroptosis occurs in an ACSL4-dependent manner in DCM. Furthermore, we demonstrate that nicotinamide mononucleotide and sulforaphane can synergistically suppress ferroptosis by targeting distinct pathways, thereby better alleviating cardiac dysfunction. Collectively, our findings uncover an FTO - ACSL4 regulatory axis that plays a crucial role in the pathogenesis of DCM, offering valuable insights for the development of therapeutic strategies against DCM.
Insights
Diabetic cardiomyopathy (DCM) involves ferroptosis. This study reveals fat mass and obesity-associated protein (FTO) inhibits ferroptosis by targeting acyl-CoA synthetase 4 (ACSL4), improving cardiac function in DCM.
Area of Science:
- Cardiology
- Metabolic Disorders
- Molecular Biology
Background:
- Diabetic cardiomyopathy (DCM) is a major complication of diabetes, with ferroptosis implicated in its pathogenesis.
- Unclear regulatory mechanisms of ferroptosis in DCM hinder therapeutic development.
Purpose of the Study:
- To investigate the role of fat mass and obesity-associated protein (FTO) in diabetic cardiomyopathy.
- To elucidate the molecular mechanisms by which FTO influences ferroptosis and cardiac function in DCM.
Main Methods:
- Investigated FTO expression in DCM models.
- Examined the effect of FTO overexpression on cardiac function and ferroptosis.
- Identified and validated acyl-CoA synthetase long-chain family 4 (ACSL4) as a direct target of FTO.
- Assessed the therapeutic potential of nicotinamide mononucleotide and sulforaphane.
Main Results:
- FTO expression was downregulated in DCM.
- FTO overexpression enhanced cardiac function by inhibiting ferroptosis.
- FTO directly targeted and inhibited ACSL4, a key mediator of ferroptosis.
- Nicotinamide mononucleotide and sulforaphane synergistically suppressed ferroptosis and alleviated cardiac dysfunction.
Conclusions:
- A novel FTO-ACSL4 regulatory axis is crucial in DCM pathogenesis.
- Targeting this axis offers potential therapeutic strategies for DCM.
- Combined therapy with nicotinamide mononucleotide and sulforaphane shows promise for DCM treatment.
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