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

## TL;DR

This study shows that ACOD1-itaconate in macrophages reduces inflammation and fibrosis in airway diseases by transferring FTH1 to fibroblasts.

## Contribution

The study identifies the ACOD1-itaconate axis as a novel metabolic regulator of inflammation and fibrosis in airway diseases.

## Key findings

- ACOD1 deficiency worsens inflammation and fibrosis in benign airway stenosis.
- 4-OI reduces oxidative stress and inflammation by upregulating FTH1 in macrophages.
- Exosomal FTH1 transfer via SCARA5 induces fibroblast ferroptosis and reduces fibrosis.

## 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.

•scRNA sequence reveals that ACOD1 is significantly upregulated during BAS.•ACOD1 deficiency aggravates acute and chronic inflammation of BAS.•Itaconate derivative 4-OI attenuates acute and chronic inflammation of BAS.•4-OI-induced high expression of FTH1 in macrophages restricts oxidative stress and acute inflammation.•Macrophage exosomal FTH1 transferred via SCARA5 induces fibroblast ferroptosis to attenuate BAS inflammation and fibrosis.

scRNA sequence reveals that ACOD1 is significantly upregulated during BAS.

ACOD1 deficiency aggravates acute and chronic inflammation of BAS.

Itaconate derivative 4-OI attenuates acute and chronic inflammation of BAS.

4-OI-induced high expression of FTH1 in macrophages restricts oxidative stress and acute inflammation.

Macrophage exosomal FTH1 transferred via SCARA5 induces fibroblast ferroptosis to attenuate BAS inflammation and fibrosis.