Artesunate attenuates sepsis-induced myocardial injury: A preliminary investigation into the JAK2/STAT3 pathway via integrated network pharmacology and experimental validation

BACKGROUND: Sepsis, a life-threatening organ dysfunction caused by a dysregulated host response to infection, frequently induces myocardial injury, which stands as one of its most common and severe complications and a key factor contributing to poor patient prognosis. This study aims to investigate the protective effect of Artesunate (AS) on sepsis-induced myocardial injury (SIMI) and to elucidate the underlying molecular mechanisms by integrating network pharmacology prediction with experimental validation. METHODS: Sepsis was induced in male Wistar rats using the cecal ligation and puncture (CLP) method, and the rats were randomly divided into five groups (n = 6/group): Ctrl, Sham, CLP, AS + CLP, and vehicle + CLP. To assess the cardioprotective effect of AS, serum levels of myocardial injury markers (BNP, LDH, CK-MB, hs-cTnI) were measured by ELISA, and myocardial histopathology was evaluated by H&E staining. The potential targets and pathways of AS against SIMI were then predicted using network pharmacology. Serum inflammatory cytokines (IL-6, TNF-α) and oxidative stress markers (SOD, MDA) were further examined by ELISA, and cardiomyocyte apoptosis was assessed by TUNEL staining. Finally, the expression of key proteins in the JAK2/STAT3 signaling pathway in myocardial tissue was determined by Western blotting to explore the underlying mechanism. RESULTS: AS significantly ameliorated pathological damage and reduced serum myocardial enzyme levels in septic rats compared to the CLP group. Network pharmacology identified 68 potential targets of AS. GO analysis revealed their primary enrichment in molecular functions such as kinase regulator activity, while KEGG enrichment analysis showed their significant association with pathways including inflammatory response. Molecular docking demonstrated favorable binding affinities between AS and core targets such as STAT3. Experimental validation further showed that AS treatment significantly decreased serum concentrations of IL-6 and TNF-α, increased SOD activity while reducing MDA content, and lowered the myocardial cell apoptosis index. Moreover, AS administration notably downregulated the protein expression levels of p-JAK2 and p-STAT3 in myocardial tissue. CONCLUSION: Based on network pharmacology prediction and experimental validation, it was demonstrated that AS protects against SIMI by inhibiting the JAK2/STAT3 signaling pathway, thereby alleviating inflammation, oxidative stress, and cardiomyocyte apoptosis. These findings provide compelling pharmacological evidence for the drug repurposing of Artesunate.