Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease in which airway macrophages (AMs) play a key role. Itaconate has emerged as a mediator of macrophage function, but its role during fibrosis is unknown. Here, we reveal that itaconate is an endogenous antifibrotic factor in the lung. Itaconate levels are reduced in bronchoalveolar lavage, and itaconate-synthesizing cis-aconitate decarboxylase expression (ACOD1) is reduced in AMs from patients with IPF compared with controls. In the murine bleomycin model of pulmonary fibrosis, Acod1^−/− mice develop persistent fibrosis, unlike wild-type (WT) littermates. Profibrotic gene expression is increased in Acod1^−/− tissue-resident AMs compared with WT, and adoptive transfer of WT monocyte-recruited AMs rescued mice from disease phenotype. Culture of lung fibroblasts with itaconate decreased proliferation and wound healing capacity, and inhaled itaconate was protective in mice in vivo. Collectively, these data identify itaconate as critical for controlling the severity of lung fibrosis, and targeting this pathway may be a viable therapeutic strategy.

特发性肺纤维化 (IPF) 是一种致命的肺部疾病，其中气道巨噬细胞 (AMs) 起关键作用。衣康酸盐已成为巨噬细胞功能的介质，但其在纤维化过程中的作用尚不清楚。在这里，我们揭示衣康酸盐是肺中的内源性抗纤维化因子。与对照组相比，IPF 患者的 AMs 中衣康酸水平在支气管肺泡灌洗液中降低，并且衣康酸合成顺式乌头酸脱羧酶表达 ( ACOD1 ) 降低。在肺纤维化的鼠博莱霉素模型中，与野生型 (WT) 同窝小鼠不同， Acod1 ^{-/-小鼠发展为持续性纤维化。}Acod1中促纤维化基因表达增加^-/-与 WT 相比，组织驻留的 AMs 和 WT 单核细胞招募的 AMs 的过继转移使小鼠免于疾病表型。用衣康酸盐培养肺成纤维细胞可降低增殖和伤口愈合能力，吸入衣康酸盐对小鼠体内具有保护作用。总的来说，这些数据确定衣康酸盐对于控制肺纤维化的严重程度至关重要，并且靶向该途径可能是一种可行的治疗策略。