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已发表论文
阿托伐他汀通过靶向 METTL3/IGF2BP1/CXCL2 通路缓解脓毒症诱导的心肌病
Authors Zhang L, Yin Y, Zheng L, Wang Y, Zhao J, Mu F , Jin F, Gong R, Wang J
Received 7 April 2025
Accepted for publication 8 September 2025
Published 21 October 2025 Volume 2025:18 Pages 14609—14628
DOI https://doi.org/10.2147/JIR.S532987
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 3
Editor who approved publication: Dr Rongxue Wu
Lulu Zhang,1,2,* Yanping Yin,1,3,* Lingling Zheng,1 Yiwen Wang,1,2 Jinyi Zhao,1 Fei Mu,1 Fuxing Jin,1,2 Rui Gong,1 Jingwen Wang1
1Department of Pharmacy, Xijing Hospital, The Fourth Military Medical University, Xi’an, People’s Republic of China; 2College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, People’s Republic of China; 3College of Life Sciences, Northwestern University, Xi’an, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Jingwen Wang, Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi’an, People’s Republic of China, Email wangjingwen8021@163.com Rui Gong, Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi’an, People’s Republic of China, Email 2682209282@qq.com
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.
Keywords: atorvastatin, sepsis-induced cardiomyopathy, m6A modification, METTL3, CXCL2
1Department of Pharmacy, Xijing Hospital, The Fourth Military Medical University, Xi’an, People’s Republic of China; 2College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, People’s Republic of China; 3College of Life Sciences, Northwestern University, Xi’an, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Jingwen Wang, Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi’an, People’s Republic of China, Email wangjingwen8021@163.com Rui Gong, Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi’an, People’s Republic of China, Email 2682209282@qq.com
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.
Keywords: atorvastatin, sepsis-induced cardiomyopathy, m6A modification, METTL3, CXCL2