Atorvastatin Alleviates Sepsis-Induced Cardiomyopathy by Targeting the METTL3/IGF2BP1/CXCL2 Pathway

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Sepsis Pathophysiology

Background:

• Sepsis-induced cardiomyopathy (SICM) is a severe complication of sepsis with complex mechanisms and limited treatment options.
• Statins, including atorvastatin (ATO), show potential in reducing sepsis mortality and organ damage, but their precise cardioprotective mechanisms in SICM remain unclear.

Purpose of the Study:

• To systematically investigate the cardioprotective effects of atorvastatin (ATO) on sepsis-induced cardiomyopathy (SICM) using in vivo and in vitro models.
• To elucidate the underlying molecular mechanisms by which ATO exerts its beneficial effects on the heart during sepsis.

Main Methods:

• Cecal ligation and puncture (CLP) model in mice pretreated with ATO to induce sepsis.
• Echocardiography for cardiac function assessment; immunohistochemistry and Western blotting for heart injury evaluation.
• Molecular docking, CETSA, DARTS, m6A-MeRIP-seq, and RNA immunoprecipitation to identify ATO target (METTL3) and elucidate the m6A modification pathway.

Main Results:

• ATO treatment significantly improved cardiac function, reduced heart tissue damage, and decreased inflammatory and myocardial injury factors in septic mice.
• ATO directly binds to and inhibits METTL3, reducing m6A modification levels in septic hearts and LPS-stimulated cardiomyocytes.
• METTL3 promotes CXCL2 expression via m6A modification of its mRNA, enhancing mRNA stability in an IGF2BP1-dependent manner, leading to inflammation and ferroptosis.

Conclusions:

• The METTL3/IGF2BP1/CXCL2 axis is identified as a key pathway promoting SICM progression.
• Atorvastatin (ATO) exerts cardioprotective effects by targeting and inhibiting this axis, offering a novel therapeutic strategy for SICM.
• This study highlights the critical role of RNA m6A modification in the pathophysiology of SICM.