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Background <p>Doxorubicin (DOX) is a highly effective chemotherapeutic agent, but its clinical application was constrained by irreversible cardiotoxicity. Increasing evidence indicates that ferroptosis is a central mechanism of DOX-induced cardiotoxicity (DIC). Both the m⁶A demethylase FTO and yes-associated protein (YAP) are found to suppress ferroptosis in DIC. Importantly, both YAP and its upstream negative regulator, MAP4K4, are potential targets of FTO. However, whether FTO regulates DOX-induced cardiac ferroptosis via the MAP4K4/YAP signaling axis remains unexplored.</p> Methods <p>FTO and YAP expressions were analyzed in DOX-treated cardiac tissues and cardiomyocytes. The effect of FTO on ferroptosis, as well as on the expression of YAP, ATF4, and MAP4K4, was evaluated in DOX-treated mouse heart and cardiomyocytes using cardiac-specific FTO AAV delivery or lentiviral transfection. Pharmacological inhibition of YAP, ATF4, or MAP4K4 was further performed to investigate the underlying mechanisms. In addition, the m⁶A modifications of FTO on MAP4K4 and YAP transcripts were examined.</p> Results <p>FTO and YAP were significantly reduced in DOX-treated cardiac tissues and cardiomyocytes. FTO overexpression markedly attenuated DIC by inhibiting ferroptosis by enhancing YAP and ATF4 expressions. Inhibition of YAP or ATF4 significantly abolished the protective and anti-ferroptotic effects of FTO. FTO also increased MAP4K4 expression, whereas MAP4K4 inhibition further enhanced the anti-ferroptotic effects mediated by the FTO/YAP/ATF4 axis. Mechanistically, FTO promoted m⁶A demethylation of MAP4K4 and YAP transcripts and enhanced their mRNA stability.</p> Conclusions <p>FTO protects against DIC by inhibiting ferroptosis via up-regulation of the YAP/ATF4 axis, and inhibition of MAP4K4 further enhances the FTO/YAP/ATF4-mediated cardioprotective and anti-ferroptotic effects.</p> Graphical Abstract <p>• DOX increases m⁶A methylation and suppresses FTO/YAP expression in the heart.</p> <p>• FTO attenuates DOX-induced ferroptosis via m⁶A-dependent upregulation of YAP.</p> <p>• FTO/YAP activates ATF4 signaling to confer cardioprotection against ferroptosis.</p> <p>• FTO upregulates MAP4K4, while MAP4K4 inhibition amplifies FTO/YAP/ATF4-mediated protection.</p> <p></p>

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MAP4K4 inhibition enhances the anti-ferroptosis effect of the FTO/YAP/ATF4 axis in doxorubicin-induced cardiotoxicity

  • 期刊论文

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  • 发表日期：

    2026年7月7日

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  • Youyou Yan,
  • Dandan Song,
  • Longbo Li,
  • Junnan Wang

摘要

Background

Doxorubicin (DOX) is a highly effective chemotherapeutic agent, but its clinical application was constrained by irreversible cardiotoxicity. Increasing evidence indicates that ferroptosis is a central mechanism of DOX-induced cardiotoxicity (DIC). Both the m⁶A demethylase FTO and yes-associated protein (YAP) are found to suppress ferroptosis in DIC. Importantly, both YAP and its upstream negative regulator, MAP4K4, are potential targets of FTO. However, whether FTO regulates DOX-induced cardiac ferroptosis via the MAP4K4/YAP signaling axis remains unexplored.

Methods

FTO and YAP expressions were analyzed in DOX-treated cardiac tissues and cardiomyocytes. The effect of FTO on ferroptosis, as well as on the expression of YAP, ATF4, and MAP4K4, was evaluated in DOX-treated mouse heart and cardiomyocytes using cardiac-specific FTO AAV delivery or lentiviral transfection. Pharmacological inhibition of YAP, ATF4, or MAP4K4 was further performed to investigate the underlying mechanisms. In addition, the m⁶A modifications of FTO on MAP4K4 and YAP transcripts were examined.

Results

FTO and YAP were significantly reduced in DOX-treated cardiac tissues and cardiomyocytes. FTO overexpression markedly attenuated DIC by inhibiting ferroptosis by enhancing YAP and ATF4 expressions. Inhibition of YAP or ATF4 significantly abolished the protective and anti-ferroptotic effects of FTO. FTO also increased MAP4K4 expression, whereas MAP4K4 inhibition further enhanced the anti-ferroptotic effects mediated by the FTO/YAP/ATF4 axis. Mechanistically, FTO promoted m⁶A demethylation of MAP4K4 and YAP transcripts and enhanced their mRNA stability.

Conclusions

FTO protects against DIC by inhibiting ferroptosis via up-regulation of the YAP/ATF4 axis, and inhibition of MAP4K4 further enhances the FTO/YAP/ATF4-mediated cardioprotective and anti-ferroptotic effects.

Graphical Abstract

• DOX increases m⁶A methylation and suppresses FTO/YAP expression in the heart.

• FTO attenuates DOX-induced ferroptosis via m⁶A-dependent upregulation of YAP.

• FTO/YAP activates ATF4 signaling to confer cardioprotection against ferroptosis.

• FTO upregulates MAP4K4, while MAP4K4 inhibition amplifies FTO/YAP/ATF4-mediated protection.