Background <p>Sarcopenia is a clinical syndrome characterized by progressive and widespread reductions in muscle mass and strength, mainly manifested by loss of muscle strength and somatic dysfunction, leading to a corresponding increased risk of falls, disability, and even death in the elderly.</p> Objective <p>This study intended to explore the role and mechanism of IRE1α-XBP1 pathway in regulating ferroptosis in age-related sarcopenia.</p> Methods <p>A mouse model of age-related sarcopenia was constructed to assess muscle function and mass. HE staining and Sirius red staining were used to observe the histopathological and morphological changes in skeletal muscle tissue, muscle fibre cross-sectional area (CSA) was determined, and immunofluorescence staining was used to detect IRE1α-XBP1 pathway proteins and 4-Hydroxynonenal (4-HNE). C2C12 cells were induced by using D-gal. Cell proliferation was detected by CCK-8, myotube diameter was observed and measured, apoptosis and ROS levels were detected by flow cytometry. Tissue and cellular iron content and oxidative stress-related indexes were detected by kits, pro-inflammatory and ferroptosis-related factors were detected by RT-qPCR, and IRE1α-XBP1 pathway proteins and 4-HNE were detected by Western blot.</p> Results <p>Activation of the IRE1α-XBP1 pathway was observed in sarcopenia mouse model, and 4μ8c, an RNase-specific inhibitor of IRE1α, effectively ameliorated the signs of aging and pathological manifestations of sarcopenia in mice. Pharmacological inhibition of the IRE1α-XBP1 pathway attenuated ferroptosis in muscle tissue of SAMP8 mice. Inhibition of IRE1α-XBP1 pathway ameliorated D-gal-induced C2C12 myotube damage and ferroptosis, and ferroptosis inducer reversed the ameliorative effects of 4μ8c on C2C12 cell ferroptosis phenotype and myotube damage.</p> Conclusion <p>Pharmacological Inhibition of IRE1α-XBP1 pathway ameliorates age-related sarcopenia by attenuating ferroptosis in SAMP8 mice.</p>