Background Drug combination presents a promising approach to surpassing the current efficacy limitations of biological agents in treating inflammatory bowel disease (IBD). Currently, ferroptosis has emerged as a novel therapeutic target for IBD. Macrophages, pivotal immune cells, also play a vital role in regulating iron metabolism within the body. Furthermore, our prior research has demonstrated that distinct macrophage subtypes exhibit varying sensitivity to reactive oxygen species (ROS) which cause ferroptosis. Combining ferroptosis inhibitors with biologics may provide a new therapeutic strategy to break the therapeutic ceiling of IBD treatment. This study aimed to investigate whether ferroptosis inhibitors could enhance the efficacy of infliximab (IFX) in treating IBD.

Methods Immunofluorescence staining was used to analyze the changes of M2 macrophages in human colon specimens pre-and post-treatment with IFX. The effect of IFX on M1 and M2 macrophage ferroptosis was investigated by RAW264.7 cell line in vitro. Additionally, the DSS-induced colitis mouse was used to evaluate the impact of ferroptosis inhibitors on IFX efficacy in vivo while further evaluating the effect of combining IFX with ferroptosis inhibitors on ferroptosis of colonic mucosal cells in mice. Immunofluorescence staining was utilized to assess the quantity of M2 macrophages post-treatment in mouse colon tissue.

Results We found that in patients who responded to IFX, M2 macrophages increased, whereas this phenomenon was not observed in non-responders, suggesting that the efficacy of IFX was closely related to M2 macrophage. Notably, our in vitro experiments demonstrated that IFX could induce ferroptosis in both M1 and M2 macrophages, while M2 macrophages were more sensitive to ferroptosis than M1. Our in vivo experimental results indicated that the treatment efficacy of IFX in combination with deferoxamine (DFO), the ferroptosis inhibitor, was superior to those using IFX alone by significantly alleviating ferroptosis in the intestinal cells of experimental colitis mice. Furthermore, IFX combined with DFO had a protective effect on M2 macrophages.

Conclusions Our study revealed that the ferroptosis inhibitor DFO could augment the therapeutic efficacy of IFX by suppressing the ferroptosis of M2 macrophages, thus providing a novel strategy for overcoming the current therapeutic ceiling of biological therapy for IBD.