Artesunate protects against sepsis-induced cardiomyopathy by reducing Akt/FoxO3-mediated apoptosis and inflammation

Sepsis-induced cardiomyopathy (SICM) is a life-threatening complication of sepsis characterized by acute and reversible myocardial dysfunction, for which effective targeted therapies remain limited. Artesunate (ART), a well-established first-line antimalarial agent, has attracted increasing attention for its anti-inflammatory, antioxidant, and cytoprotective properties. However, its role in SICM has not been fully elucidated. In this study, a murine SICM model is established using lipopolysaccharide (LPS) to evaluate the effects of ART on animal mortality, cardiac function, histopathology, and biomarkers of myocardial injury. In parallel, the in vitro study is performed using neonatal rat cardiomyocytes (NRCMs) and H9c2 cells exposed to LPS in the presence or absence of ART. Transcriptomic and metabolomic analyses are employed to elucidate the molecular mechanisms underlying ART-mediated cardioprotection. ART administration significantly improves cardiac function, attenuates myocardial injury, alleviates the inflammatory response, and reduces cardiomyocyte apoptosis in LPS-challenged mice. Consistent results are observed in vitro. Integrated multi-omics analyses identify the Akt/FoxO3 signaling pathway as a critical target of ART. ART treatment contributes to increased Akt phosphorylation and subsequent suppression of FoxO3 nuclear translocation and its transcriptional activity. Pharmacological inhibition of Akt using MK2206 or genetic knockdown of FoxO3 by siRNA abolishes the cardioprotective effects of ART. In addition, molecular docking analysis suggests a potential interaction between ART and Akt isoforms. Collectively, these findings demonstrate that ART possesses significant cardioprotective effects in experimental SICM through modulation of the Akt/FoxO3 signaling axis, leading to reduced apoptosis and inflammation. ART may serve as a therapeutic candidate for the management of SICM.