Enhancing the therapeutic effect of infliximab by inhibiting ferroptosis of M2 macrophages in experimental colitis

Objective 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. Therefore, combining ferroptosis inhibitors with biologics may provide a new therapeutic strategy to break the therapeutic ceiling of IBD treatment. Thus, this study investigated whether ferroptosis inhibitors could enhance infliximab (IFX) efficacy on IBD. Methods Immunofluorescence was used to analyze M2 macrophages in human colon specimens pre- and post-IFX treatment. The effect of IFX on ferroptosis of M1 and M2 macrophages was assessed on RAW264.7 in vitro. Moreover, a DSS-induced colitis mouse model was employed to evaluate the impact of ferroptosis inhibitors on IFX efficacy in vivo. Results Although M2 macrophages were increased in patients who responded to IFX treatment, there was no concurrent increase in non-responders which suggested that the efficacy of IFX was closely related to M2 macrophage. Notably, IFX enhanced ferroptosis in M1 and M2 macrophages in vitro, while M2 macrophages were more sensitive to ferroptosis than M1 macrophages. Finally, the ferroptosis inhibitor deferoxamine enhanced IFX efficacy by significantly alleviating mucosa ferroptosis in experimental colitis mice and also had a protective effect on M2 macrophages undergoing IFX. Conclusions The current results suggested that ferroptosis inhibitors could enhance the therapeutic efficacy of IFX by rescuing M2 macrophages from ferroptosis, thereby offering a new strategy for overcoming the current therapeutic ceiling of IBD biologic therapy.