Serum irisin levels are decreased in patients with sepsis, and exogenous irisin suppresses ferroptosis in the liver of septic mice

BACKGROUND: Sepsis remains a major health issue without an effective therapy. Ferroptosis, an iron‐dependent programmed cell death, has been proposed to be related to the pathogenesis of sepsis. Irisin, a myokine released during exercise, improves mitochondrial function under various conditions. Ferroptosis is closely related to mitochondrial function. However, the role of irisin in sepsis‐induced ferroptosis and mitochondrial dysfunction in the liver remained unknown. Thus, we hypothesize that irisin treatment suppresses ferroptosis and improves mitochondrial function in sepsis. METHODS: To study this, we first explored the role of serum irisin levels in patients with sepsis, and then determined the effect of irisin administration on ferroptosis and mitochondrial function in the liver of septic mice. RESULTS: Serum irisin levels were decreased and negatively correlated with the APACHE II scores in patients with sepsis. In mice subjected to cecal ligation and puncture (CLP), exogenous irisin administration suppressed ferroptosis, inhibited inflammatory response, decreased reactive oxygen species (ROS) production, restored abnormal mitochondrial morphology, and increased mtDNA copy number and adenosine triphosphate (ATP) content. The effect of irisin on ferroptosis was confirmed in LPS‐treated hepatocytes and CLP‐induced septic mice. Inhibition of glutathione peroxidase 4 (GPX4), a central regulator of ferroptosis, reduced irisin's protective effects in LPS‐treated hepatocytes and CLP‐induced septic mice, while blocking the irisin receptor with RGD peptide or Echistain decreased irisin‐induced GPX4 expression. CONCLUSIONS: Serum irisin levels are decreased and negatively correlated with disease severity in patients with sepsis, and irisin treatment suppresses ferroptosis and restores mitochondrial function in experimental sepsis. Irisin may offer therapeutic potential in the management of sepsis.