IL4I1 attenuates myocardial infarction by inhibiting macrophage ferroptosis via the I3P/AHR/NRF2 signaling pathway

BACKGROUNDS: As an immunometabolic enzyme, Interleukin-4 induced gene 1 (IL4I1) catalyzes aromatic amino acid degradation to modulate immune functions. Our prior work demonstrated that IL4I1 promotes anti-inflammatory macrophage polarization, thereby attenuating atherosclerosis progression-a key pathological precursor to myocardial infarction (MI). Despite this established role in plaque development, the functional significance of this immunometabolic enzyme in post-MI cardiac injury remains unexplored. METHODS: In murine MI models, we determined the cellular localization of IL4I1 expression. IL4I1-knockout (KO) and wild-type mice were evaluated for survival, cardiac function, fibrosis, inflammation, and ferroptosis markers. In vitro, cytoprotection by IL4I1 metabolites against hypoxia-induced ferroptosis was tested in macrophages. For therapeutic evaluation, IL4I1-KO mice received intraperitoneal indole-3-pyruvic acid (I3P). RESULTS: IL4I1 expression was significantly upregulated post-MI, peaking at day 3 and predominantly localized to macrophages. IL4I1-KO mice exhibited increased mortality, worsened cardiac dysfunction, aggravated fibrosis, amplified inflammation, and enhanced ferroptosis. In vitro, IL4I1-produced I3P rescued hypoxic macrophages by suppressing reactive oxygen species production, lipid peroxidation, and restoring FTH-1/GPX4 via AHR nuclear translocation. Mechanistically, I3P promoted AHR nuclear translocation, activating the NRF2 pathway. This protective effect was abolished by AHR inhibition. Critically, I3P administration rescued these impairments in IL4I1-KO mice. CONCLUSION: We identify a novel cardioprotective axis wherein macrophage-derived IL4I1 catalyzes the production of I3P, activating AHR-NRF2 signaling to suppress ferroptosis, thereby mitigating post-MI inflammation, adverse remodeling, and cardiac dysfunction. Targeting IL4I1 and I3P represents a promising therapeutic strategy for ischemic heart disease.