Cordycepin alleviates sepsis-induced cardiomyopathy by attenuating mitochondrial oxidative stress and apoptosis through modulation of the PI3K/Akt/mTOR pathway

OBJECTIVE: Sepsis-induced cardiomyopathy (SICM) is a frequent and life-threatening complication of sepsis, characterized by acute cardiac dysfunction and high mortality, yet no specific therapy is currently available. Cordycepin (COR), a natural bioactive compound, has been reported to exert anti-inflammatory and cardioprotective effects; however, its role and underlying mechanisms in SICM remain unclear. METHODS: SICM was established in mice by intraperitoneal lipopolysaccharide (LPS) injection or cecal ligation and puncture (CLP). In vitro, HL-1 cells were treated with cytokine mixtures. COR was administered as a pre-treatment in both models. Cardiac function and myocardial injury were evaluated by echocardiography, histopathology, and biochemical assays. Transcriptome sequencing was performed to identify potential pathways, followed by validation using Western blotting and immunofluorescence. Mitochondrial function and cell death were assessed using CCK-8, flow cytometry, JC-1 staining, MitoTracker labeling, and transmission electron microscopy. RESULTS: COR markedly attenuated myocardial injury induced by LPS, CLP, and cytokine stimulation. Compared with the model group, COR improved cardiac function, increased 7-day survival, and reduced myocardial inflammatory responses. Transcriptomic profiling implicated PI3K/Akt/mTOR signaling, and subsequent in vivo and in vitro experiments supported pathway activation by COR. Mechanistically, COR restored mitochondrial homeostasis and alleviated oxidative stress, evidenced by decreased ROS and MDA and increased SOD activity, while enhancing mitochondrial membrane potential and ATP production. COR also suppressed cardiomyocyte apoptosis, reflected by reduced Bax expression and decreased ratios of Cleaved Caspase-3/Caspase-3 and Cleaved Caspase-9/Caspase-9, along with increased Bcl-2 expression. CONCLUSION: COR mitigates inflammation, oxidative stress, and cardiomyocyte apoptosis in SICM via modulation of the PI3K/Akt/mTOR pathway, thereby attenuating myocardial injury and improving cardiac function. Collectively, these findings indicate that COR may serve as a potential novel therapeutic agent for the management of SICM.