ObjectiveAcute lung injury is a fatal complication triggered by sepsis, characterized by widespread inflammation and weakening of the alveolar epithelium. Irisin has been reported to exert anti-inflammatory effects, which are produced by the cleavage of fibronectin type III domain-containing protein 5 in skeletal muscle. Here, we investigated the potential of irisin in preventing acute lung injury by protecting the alveolar epithelium.MethodsThe sepsis-related acute lung injury model was established by a cecal ligation and puncture model in C57/BL6N mice. Lung histology was assessed using hematoxylin and eosin and Masson staining. Ferroptosis-related proteins and genes were quantified via western blot and quantitative polymerase chain reaction, respectively, whereas cytokine levels were measured using enzyme-linked immunosorbent assay.ResultsHistological analysis revealed lung injury in the cecal ligation and puncture group, alongside elevated levels of cytokines such as IL-1β, IL-18, and TNF-α compared with controls. Treatment with irisin mitigated sepsis-induced lung damage and reduced oxidative stress, as indicated by reactive oxygen species and Fe levels. Furthermore, irisin pretreatment inhibited the upregulation of ferroptosis-related genes (, , and ) as well as ACSL4, COX-2, and p-AMPK expression.ConclusionThese findings suggest that irisin treatment is associated with reduced ferroptosis and inflammation in sepsis-induced acute lung injury. Irisin emerges as a promising candidate for acute lung injury therapy induced by sepsis.