Yan Xiaochen, Jiang Peng, Li Changqing, Liu Fengjuan, Fu Ping, Liu Dengqun, Du Xi, Ma Li, Wang Tong, Yuan Xin, Ye Shengliang, Wang Zongkui
Institute of Blood Transfusion, Chinese Academy of Medical Sciences & Peking Union Medical College, 610052, Chengdu, China.
Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, 610041, Chengdu, China.
Apoptosis. 2025 Apr;30(3-4):734-750. doi: 10.1007/s10495-024-02064-y. Epub 2024 Dec 25.
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.
化疗引起的粘膜炎（CIM）显著影响生活质量，并降低接受特定化疗药物治疗患者的生存率。然而，CIM的有效临床治疗方法仍然有限。静脉注射免疫球蛋白（IVIg）是一种从混合人血浆中提取的治疗药物，广泛用于治疗炎症性疾病。本研究旨在评估IVIg对CIM的治疗效果及其潜在机制。
采用阿霉素（Dox）诱导的小鼠肠道粘膜炎模型和小肠损伤类器官模型，探讨IVIg对CIM的保护作用。采用免疫染色、透射电子显微镜（TEM）、蛋白质免疫印迹法（WB）和蛋白质组学分析，进一步研究肠上皮细胞中的铁死亡及其潜在机制。
在Dox诱导的小鼠肠道粘膜炎模型中，肠上皮屏障被破坏，铁死亡增加，表现为体重减轻、血液学损伤、炎症、肠上皮细胞线粒体萎缩、脂质过氧化、紧密连接受损和肠微绒毛损伤。IVIg治疗在体外和体内均显著改善了肠上皮屏障损伤并减少了铁死亡。蛋白质组学分析显示，FcγR介导的吞噬信号通路参与了IVIg对CIM小鼠的治疗作用。WB结果表明，该通路下游的关键蛋白Syk、PI3K和Akt在CIM小鼠中磷酸化增加，而IVIg治疗显著降低了磷酸化水平。此外，740Y-P（一种PI3K激活剂）或SC79（一种Akt激活剂）可逆转IVIg对Dox诱导的Syk/PI3K/Akt轴激活和铁死亡的抑制作用，以及其对肠道炎症和肠屏障损伤的保护作用。
我们的研究结果表明，IVIg通过Syk/PI3K/Akt轴抑制铁死亡来改善CIM。这些结果表明，IVIg可能是一种治疗CIM的潜在方法。
