Artesunate does not prevent cardiac hypertrophy but inhibits heart failure progression in mice.

Heart failure (HF) poses a substantial challenge to healthcare systems globally, particularly at the advanced stages of various cardiac diseases, due to its high morbidity and mortality rates. This study aimed to assess the therapeutic potential of artesunate in a mouse model of HF induced by isoprenaline. Adult male C57BL/6J mice were subcutaneously injected with isoprenaline (50 mg/kg/day) for 14 consecutive days, with artesunate administered during the last 7 days. Strikingly, late-phase intervention with artesunate retarded the decline of cardiac function and attenuated lung congestion in HF mice. Although it did not ameliorate cardiac hypertrophy, as indicated by unchanged heart weight and myocyte cross-sectional area, artesunate markedly alleviated interstitial fibrosis and downregulated mRNA expression of Tgfb1 and Col1a1 in failing hearts. Mechanistically, artesunate suppressed myocardial infiltration of monocytes/macrophages and downregulated key inflammatory genes, including Ccl2, Il6, Nos2, Il1b, and Tnf. Furthermore, it elevated protein levels of Nrf2, glutathione peroxidase 4, and heme oxygenase-1, and suppressed ferroptosis in failing hearts. In summary, late-phase intervention with artesunate slows HF progression in mice by mitigating myocardial inflammation, fibrosis, and ferroptosis, independent of hypertrophy regression. SIGNIFICANCE STATEMENT: Although late-phase intervention with artesunate does not impact cardiac hypertrophy, it reduces myocardial inflammation and fibrosis, slowing heart failure progression. Our findings provide compelling evidence for artesunate as a promising therapeutic candidate, with its efficacy in a clinically relevant experimental context underscoring its significant translational potential.