FTO ameliorates doxorubicin-induced cardiotoxicity by inhibiting ferroptosis via P53-P21/Nrf2 activation in a HuR-dependent m6A manner
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View abstract on PubMed
Summary
This summary is machine-generated.Fat mass and obesity-associated protein (FTO) protects against doxorubicin-induced cardiotoxicity by inhibiting ferroptosis. FTO upregulates P21/Nrf2, crucial for this protective effect, forming a feedback loop with HuR and P53.
Area Of Science
- Biochemistry
- Molecular Biology
- Cardiology
Background
- Doxorubicin (DOX) chemotherapy causes cardiotoxicity, limiting its use.
- Ferroptosis, a type of cell death driven by lipid peroxidation, is a key mechanism in DOX-induced cardiotoxicity.
- N6-methyladenosine (m6A) RNA modification influences DOX-induced ferroptosis, but its precise role is unclear.
Purpose Of The Study
- To investigate the role of m6A modification, specifically the fat mass and obesity-associated protein (FTO), in DOX-induced cardiotoxicity.
- To elucidate the underlying molecular mechanisms involving P21 and Nrf2 in FTO-mediated protection against ferroptosis.
Main Methods
- Investigated FTO expression in DOX-treated mouse hearts and H9C2 cells.
- Assessed the effects of FTO overexpression on cardiac function, cell viability, and ferroptosis markers.
- Utilized P21 and Fer-1 (ferroptosis inhibitor) to evaluate their roles.
- Examined the involvement of P53 and Human antigen R (HuR) using genetic manipulation and RNA immunoprecipitation assays.
Main Results
- FTO downregulation correlated with DOX-induced cardiotoxicity.
- FTO overexpression improved cardiac function and cell viability, inhibiting ferroptosis.
- FTO upregulated P21 and activated Nrf2, mediating protection via P53-dependent or independent pathways.
- HuR was essential for FTO's regulation of ferroptosis and the P53-P21/Nrf2 axis.
- A positive feedback loop involving FTO, HuR, and P53-P21 was identified.
Conclusions
- FTO inhibits DOX-induced ferroptosis and cardiotoxicity by activating the P21/Nrf2 pathway through m6A demethylation.
- The FTO-HuR-P53-P21 axis represents a novel therapeutic target for mitigating DOX-induced cardiotoxicity.
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