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

Background: Sepsis-induced cardiomyopathy (SICM) is a common and serious complication in patients with sepsis and septic shock. Its pathological and physiological mechanisms are highly complex and often lead to dysfunction of multiple organ systems, and the current clinical intervention strategies have limited efficacy. Statins have been shown to reduce mortality of sepsis patients and alleviate multi-organ damage caused by sepsis, including SICM. However, the molecular mechanisms by which atorvastatin (ATO) exerts cardioprotective effects have not been fully elucidated. This study aims to systematically explore the cardioprotective effect of ATO on SICM through in vivo and in vitro experiments, and to elucidate the molecular mechanism underlying ATO's cardioprotective effects.

Methods: Mice were exposed to multi-bacterial sepsis through cecal ligation and puncture (CLP) surgery, and were continuously pretreated with ATO for 6 days before surgery. Cardiac function was evaluated by echocardiography. Immunohistochemistry and Western blotting were used to investigate the protective effect of ATO on heart injury in septic mice. AutoDock software, CETSA and DARTS experiments were used to verify the specific binding of ATO to METTL3. Furthermore, the regulatory role of METTL3-mediated m⁶A modification in septic myocardial inflammatory injury and its molecular mechanisms were elucidated by m⁶A-MeRIP-seq, RNA immunoprecipitation and Western blotting.

Results: ATO could obviously improve the cardiac function of septic mice, alleviate the heart tissue damage, and inhibit the release of inflammatory factors and myocardial injury factors. Mechanically, ATO binds to METTL3 with high affinity and inhibits its expression, thereby suppressing the overall m⁶A modification level in heart tissue of septic mice and in lipopolysaccharide (LPS)-stimulated cardiomyocytes. Importantly, METTL3 promoted CXCL2 expression by mediating m⁶A modification of CXCL2 mRNA and enhancing the stability of CXCL2 mRNA in an IGF2BP1 dependent manner. The high expression of CXCL2 eventually triggers the inflammatory response and Ferroptosis of cardiomyocytes, resulting in septic myocardial injury.

Conclusion: This study elucidates that the METTL3 (m⁶A)/IGF2BP1/CXCL2 axis promotes the pathological progression of SICM, and ATO exerts cardioprotective effects by targeting this pathway, providing new insights into the significance of RNA m⁶A modification in SICM.

CXCL2; METTL3; atorvastatin; m6A modification; sepsis-induced cardiomyopathy.