Chemotherapy-induced mucositis (CIM) significantly impacts quality of life and reduces survival in patients treated with specific chemotherapeutic agents. However, effective clinical treatments for CIM remain limited. Intravenous immunoglobulin (IVIg), a therapeutic derived from pooled human plasma, is widely used to treat inflammatory diseases. This study aimed to evaluate the therapeutic efficacy and underlying mechanisms of IVIg in CIM.A murine model of doxorubicin (Dox)-induced intestinal mucositis and an organoid model of small intestinal injury were used to explore the protective effects of IVIg on CIM. Immunostaining, transmission electron microscopy (TEM), western blotting (WB), and proteomic analysis were used to further investigate ferroptosis in intestinal epithelial cells and the underlying mechanisms.In the murine model of Dox-induced intestinal mucositis, intestinal epithelial barrier was destroyed and ferroptosis increased, characterized by weight loss, hematological injury, inflammation, mitochondrial atrophy in intestinal epithelial cells, lipid peroxidation, impairment of tight junctions, and damage to intestinal microvilli. IVIg treatment significantly ameliorated intestinal epithelial barrier damage and reduced ferroptosis both in vitro and in vivo. Proteomic analysis revealed that the FcγR-mediated phagocytosis signaling pathway was involved in the therapeutic effects of IVIg on CIM mice. WB results demonstrated that key proteins downstream of this pathway, Syk, PI3K, and Akt, showed increased phosphorylation in CIM mice, whereas IVIg treatment significantly reduced the phosphorylation levels. Furthermore, the inhibitory effects of IVIg on Dox-induced activation of the Syk/PI3K/Akt axis and ferroptosis, as well as its protective effects on intestinal inflammation and intestinal barrier damage, were reversed by 740Y-P (an PI3K activator) or SC79 (an Akt activator).Our findings highlight that IVIg ameliorates CIM by inhibiting ferroptosis via the Syk/PI3K/Akt axis. These results suggest that IVIg may represent a potential therapeutic approach for CIM.© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.