{
  "abstract": "Background Many patients with inflammatory bowel disease (IBD) exhibit non-response to biologic therapies such as infliximab (IFX), underscoring the need for combination strategies. Ferroptosis, a form of cell death driven by lipid peroxidation, has emerged as a therapeutic target in IBD. Macrophages are central to intestinal immune balance and oxidative stress. We previously demonstrated differential sensitivity of macrophage subsets to ferroptosis. Notably, M2 macrophages (M2) promote inflammation resolution but remain vulnerable to ferroptosis. We therefore investigated whether ferroptosis inhibitors could enhance IFX efficacy through modulation of macrophage ferroptosis and explored the underlying mechanisms.Methods Public single-cell and bulk transcriptomic datasets were integrated with immunofluorescence to identify effector cells associated with IFX response. In a DSS-induced colitis model, the therapeutic effects of IFX alone or combined with the ferroptosis inhibitor deferoxamine (DFO) were evaluated. Macrophage subset distribution and ferroptosis-related markers in colonic M2 were also assessed. M2 sorted from IFX- and IFX+DFO–treated mice underwent Smart-seq RNA sequencing and pathway enrichment analysis to identify candidate regulatory pathways. Mechanistic validation was performed in vitro using M2-polarized BMDMs with gene knockdown and overexpression. Lipid peroxidation, cell viability, and iron metabolism were measured to evaluate their roles in DFO-mediated protection.Results Our results identified M2 as the key effector cell population associated with IFX response. Although IFX reduced inflammation, it failed to effectively attenuate ferroptosis in M2. In the DSS-induced colitis model, we found that the combined treatment with DFO significantly enhanced the efficacy of IFX. Our further mechanistic analyses showed that DFO markedly reduced ferroptosis in colonic tissue and M2 and increased the M2 proportion, thereby restoring the M1/M2 balance. Our transcriptome analysis revealed enrichment of redox and glutathione metabolism pathways in IFX+DFO–treated M2. Integrative network analysis further identified NQO1 as a central regulator. Our functional assays demonstrated that NQO1 knockdown impaired DFO-mediated protection, whereas NQO1 overexpression partially recapitulated this effect. We further confirmed that Nrf2 acts upstream of NQO1.Conclusions Our study demonstrates that ferroptosis inhibition via the Nrf2/NQO1 axis restores M2 function and enhances IFX therapeutic response, suggesting a novel combinatorial strategy to overcome biologic resistance in IBD.",
  "authors": [
    {
      "affiliations": [
        "Tianjin Medical University General Hospital, China"
      ],
      "name": "Zelin Feng"
    },
    {
      "affiliations": [
        "Tianjin Medical University General Hospital, China"
      ],
      "name": "Huizhen Li"
    },
    {
      "affiliations": [
        "Tianjin Medical University General Hospital, China"
      ],
      "name": "Qinghua Yi"
    },
    {
      "affiliations": [
        "Tianjin Medical University General Hospital, China"
      ],
      "name": "Qiuyue Tu"
    },
    {
      "affiliations": [
        "Tianjin Medical University General Hospital, China"
      ],
      "name": "Xinyue Wei"
    },
    {
      "affiliations": [
        "Tianjin Medical University General Hospital, China"
      ],
      "name": "Haojia Lin"
    },
    {
      "affiliations": [
        "Tianjin Medical University General Hospital, China"
      ],
      "name": "Yanru Zhang"
    },
    {
      "affiliations": [
        "Tianjin Medical University General Hospital, China"
      ],
      "name": "Hetong Zhang"
    },
    {
      "affiliations": [
        "Southern Medical University Shenzhen Hospital, China"
      ],
      "name": "Xiaocang Cao"
    }
  ],
  "title": "IDDF2026-ABS-0148 Ferroptosis inhibition enhances the therapeutic efficacy of infliximab in experimental colitis via Nrf2/NQO1-dependent preservation of M2 macrophages",
  "uid": "f4b64cd8-bad2-5389-9bbe-b8e7438866ee"
}