m⁶A demethylase ALKBH5 attenuates doxorubicin-induced cardiotoxicity via posttranscriptional stabilization of Rasal3

Area of Science:

• Biochemistry
• Molecular Biology
• Cardiology

Background:

• Anthracyclines like doxorubicin (DOX) cause cardiotoxicity, limiting their clinical use.
• N6-methyladenosine (m⁶A) modification is crucial in biological processes, but its role in DOX-induced cardiotoxicity (DIC) is unknown.
• The function of the m⁶A demethylase ALKBH5 in DIC is also unclear.

Purpose of the Study:

• To investigate the role of ALKBH5 in DOX-induced cardiotoxicity (DIC).
• To elucidate the underlying molecular mechanisms of ALKBH5 in protecting against DIC.

Main Methods:

• Constructed DIC mouse models using Alkbh5-knockout (KO), knockin (KI), and myocardial-specific KO mice.
• Assessed cardiac function and DOX-mediated signal transduction.
• Investigated the effect of ALKBH5 overexpression on DOX-induced injury.

Main Results:

• Alkbh5 deficiency aggravated DIC, increasing mortality and mitochondrial damage.
• ALKBH5 overexpression improved cardiac function, survival, and alleviated mitochondrial injury.
• ALKBH5 regulated Rasal3 expression in an m⁶A-dependent manner, activating the RAS/RAF/ERK pathway and inhibiting apoptosis.

Conclusions:

• ALKBH5 plays a protective role against DOX-induced cardiotoxicity (DIC).
• ALKBH5 functions by regulating Rasal3 mRNA stability and activating the RAS/RAF/ERK signaling pathway.
• ALKBH5 demonstrates potential as a therapeutic target for DIC.