ACOD-itaconate in macrophage attenuates oxidative stress and inflammation in benign airway stenosis by upregulating and transferring FTH1.

Abstract

The oxidative stress of macrophage plays pivotal roles of acute and chronic inflammation and chronic fibrotic phases, in which the metabolic mechanism needs to be further explored. In our research, multi-omics analyses of human and murine during Benign airway stenosis (BAS) biopsy identified ACOD1 as a hallmark of immunometabolic regulation during acute inflammation stage. ACOD1 knockout aggravated both acute and chronic inflammation, which increased the granulation tissue formation. The ACOD1-itaconate axis, along with its derivative, 4-octyl itaconate (4-OI), orchestrated acute and chronic inflammation, which attenuated the fibrosis of BAS. 4-OI upregulated FTH1 expression in macrophages by activating NRF2, which effectively suppressed oxidative stress and acute inflammation. Furthermore, 4-OI promoted the packaging of FTH1 into macrophage-derived exosomes, which were transferred to fibroblasts in a SCARA5-dependent manner, inducing fibroblast ferroptosis and alleviating chronic fibrosis. In sum, this study illustrates that the ACOD1-itaconate metabolic axis decreases oxidative stress and inflammation in macrophage, which attenuates fibrosis by inducing FTH1 transfer, offering a therapeutic target for fibrotic airway diseases.

Key Findings

• ACOD1 is a hallmark of immunometabolic regulation during the acute inflammation stage in benign airway stenosis.
• The ACOD1-itaconate axis and its derivative 4-octyl itaconate (4-OI) attenuate acute and chronic inflammation and fibrosis by activating NRF2 and upregulating FTH1 expression in macrophages.
• 4-OI promotes the transfer of FTH1 via macrophage-derived exosomes to fibroblasts, inducing ferroptosis and alleviating chronic fibrosis.

Clinical Significance

Citation

Chen YiLin, Xu ChengFei, Luo Taoet al.. ACOD-itaconate in macrophage attenuates oxidative stress and inflammation in benign airway stenosis by upregulating and transferring FTH1. Redox biology. 2026-Mar-20.