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Sirtuin 4 knockout exacerbates cardiac injury in septic cardiomyopathy via activating the MAPK-JNK pathway
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DOI：10.1186/s10020-026-01586-2.png)
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Abstract
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Septic cardiomyopathy (SCM) significantly contributes to mortality among septic patients, and its mechanism is closely related to abnormal inflammatory responses. Previous studies revealed the essential role of the Sirtuin4 gene in cardiomyocyte and myocardial function; however, the precise mechanisms underlying its involvement in SCM remain poorly understood. Sepsis model was established by cecal ligation and puncture (CLP) in vivo. Survival rate and sepsis score were assessed. Myocardial function was evaluated by echocardiography, serum creatine kinase isoenzyme (CK-MB) concentration and TUNEL staining. In vitro, mouse cardiomyocytes HL-1 cell line was stimulated with lipopolysaccharide (LPS) to simulate an inflammatory environment. Transcriptomic sequencing identified differentially expressed genes (DEGs) and enriched signaling pathways in hearts from SIRT4-knockout CLP mice, and validated by Western blot and immunofluorescence. The expression of SIRT4 was significantly downregulated in both CLP-induced myocardium and LPS-treated HL-1 cells. SIRT4 knockout exacerbated CLP-induced mortality and myocardial dysfunction. Furthermore, transcriptomic and molecular biology experiments revealed that SIRT4 deficiency sharply activated the MAPK-JNK pathway. In vitro experiments further validated that SIRT4 knockdown aggravated LPS-induced inflammation in cardiomyocytes by activating the MAPK-JNK pathway. Conversely, inhibiting JNK effectively attenuated both the MAPK-JNK pathway activation and the cellular damage caused by SIRT4 deficiency. Additionally, SIRT4 deficiency activated the mediator AMPK, thereby upregulating the MAPK-JNK pathway in SCM. SIRT4 knockout exacerbates cardiac injury in septic cardiomyopathy by activating the MAPK-JNK pathway, suggesting SIRT4 is a potential therapeutic target for sepsis-induced cardiomyopathy.
Keywords:
Sirtuin4 (SIRT4)
Septic cardiomyopathy
The MAPK‒JNK pathway
Inflammation
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