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<p>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.</p> Graphical abstract <p></p> <p>Schematic representation of FTO-mediated mitigation of ferroptosis occurs in an ACSL4-dependent manner in diabetic cardiomyopathy (DCM). FTO is downregulated in DCM, which leads to increased methylation of <i>Acsl4</i> transcripts. This epigenetic modification results in elevated levels of <i>Acsl4</i> mRNA and ACSL4 protein, which subsequently induces lipid peroxidation and ferroptosis. The attenuation of FTO-mediated ferroptosis is thus achieved through an ACSL4-dependent manner. Importantly, based on our previous study, NMN targeting FTO combined with SFN targeting NRF2 could synergistically inhibit ferroptosis, reducing lipid peroxidation and ferroptosis, and ultimately ameliorating DCM. DM, diabetes mellitus; FTO, fat mass and obesity-associated protein; DCM, diabetic cardiomyopathy; ACSL4, acyl-CoA synthetase long-chain family member 4; SLC7A11, solute carrier family 7 member 11; NMN, mononucleotide; SFN, sulforaphane</p>

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FTO-Mediated Mitigation of Ferroptosis Occurs in an ACSL4-Dependent Manner in Diabetic Cardiomyopathy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月18日

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  • Xin-xin Chen,
  • Yan Gu,
  • Zhe Yin,
  • Yu-tang Li,
  • Zhan-chuan Ma,
  • Wei Wang,
  • Yun-qing Hou,
  • Xiang Wang

摘要

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.

Graphical abstract

Schematic representation of FTO-mediated mitigation of ferroptosis occurs in an ACSL4-dependent manner in diabetic cardiomyopathy (DCM). FTO is downregulated in DCM, which leads to increased methylation of Acsl4 transcripts. This epigenetic modification results in elevated levels of Acsl4 mRNA and ACSL4 protein, which subsequently induces lipid peroxidation and ferroptosis. The attenuation of FTO-mediated ferroptosis is thus achieved through an ACSL4-dependent manner. Importantly, based on our previous study, NMN targeting FTO combined with SFN targeting NRF2 could synergistically inhibit ferroptosis, reducing lipid peroxidation and ferroptosis, and ultimately ameliorating DCM. DM, diabetes mellitus; FTO, fat mass and obesity-associated protein; DCM, diabetic cardiomyopathy; ACSL4, acyl-CoA synthetase long-chain family member 4; SLC7A11, solute carrier family 7 member 11; NMN, mononucleotide; SFN, sulforaphane