Objective To investigate the role of irisin on doxorubicin(DOX)-induced cardiac injury and its mechanism.Methods Thirty male C57BL/6J mice were selected and randomly divided into blank group,DOX group and irisin treatment group,with 10mice in each group.Myocardial injury was induced by intraperitoneal injection of DOX(5mg/kg)every five days,with a total of 20mg/kg;the blank group was given an equal proportion of normal saline;the irisin treatment group was injected intraperitoneally with iri-sin[1mg/(kg·d)]every day for one week in advance,and irisin(1mg/kg)was injected at the same time as the DOX treatment.The survival rate was recorded during the experiment,and the surviving mice were tested for cardiac function on the twenty-first day,and the ratio of heart weight to tibia length was calculated.Enzyme-linked immunosorbent assay(ELISA)was used to detect the plasma creatine kinase isoenzyme(CK-MB),lactate dehydrogenase(LDH),and cardiac troponin(cTnT)levels;hematoxylin-eosin(HE)staining was used to observe the myocardial structure;Masson staining was used to observe the myocardial fibrosis;and kit was used to detect myo-cardial malondialdehyde(MDA),reduced glutathione/oxidized glutathione(GSH/GSSG)levels and superoxide dismutase(SOD)activi-ty;real-time fluorescence quantitative polymerase chain reaction(RT-qPCR)was used to detect cardiac inflammatory factors interleu-kin-1 β(IL-1 β),interleukin-6(IL-6)and tumor necrosis factor-α(TNF-α)expression;Western blot was used to detect pro-tein kinase B(Akt)and its phosphorylation(p-Akt)level,nuclear transcription-related factor 2(Nrf2)and glutathione oxidase 4(GPx4)and acyl-CoA synthetase long chain family member 4(ACSL4)levels.Results The survival rate of DOX group was de-creased,left ventricular ejection fraction and short-axis shortening rate were significantly lower than those in the blank group,left ven-tricular end-diastolic volume was increased,the ratio of heart weight to tibia length was decreased,and the plasma CK-MB,LDH,and cTnT were increased,accompanied by tissue edema,inflammatory infiltration,and fibroplasia.Meanwhile,cardiac MDA and GSSG con-tents were higher in the DOX group than those in the blank group,while the GSH levels and SOD activity were lower than those in the blank group,accompanied by high levels of inflammation and oxidative stress.In the irisin treatment group,the survival rate was in-creased,cardiac injury and dysfunction were alleviated,oxidative stress and inflammatory injury were reduced,accompanied by an in-crease in the level of p-Akt,the expression of Nrf2 and GPx4 was up-regulated,and the expression of ACSL4 was inhibited.Conclu-sion Irisin up-regulates Akt/Nrf2,inhibits ferroptosis,alleviates DOX-induced cardiac inflammation and oxidative stress,and im-proves cardiac injury.