Huangfu Shuchen, Lan Chaoting, Li Sitao, Wang Huijuan, Yan Chun, Yang Yuling, Tian Bowen, Mu Yide, Zhao Peizhi, Tian Yan, Wang Yijia, Zhong Wei, Zhong Limei, Shi Yongyan, Liu Yufeng
Center for Medical Research on Innovation and Translation, Guangzhou First People' s Hospital, the Second Affiliated Hospital of South China University of Technology, Guangzhou, Guangdong, China.
Department of Pediatric Surgery, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, Guangdong, China.
Clin Transl Med. 2025 Jul;15(7):e70419. doi: 10.1002/ctm2.70419.
Necrotizing enterocolitis (NEC) is a rapidly progressive and severe gastrointestinal disorder in neonates that is marked by an inflammatory cascade initiated by mechanisms that remain incompletely understood, resulting in intestinal necrosis and systemic infections. This study demonstrated that itaconate (ITA) exerts a protective effect in NEC by regulating macrophage reprogramming.
Changes in ITA expression were investigated using immunofluorescence staining and liquid chromatography-mass spectrometry, and their effect on immune cell differentiation was verified through single-cell sequencing. In vivo experiments were performed using ACOD1 and ACOD1LysM NEC mouse models.
We detected changes in ITA expression in clinical NEC samples and confirmed the effect of these changes on immune cell differentiation. In vivo experiments confirmed the therapeutic role of ITA in regulating macrophage differentiation in NEC, and we further investigated the mechanism by which ITA regulates macrophage metabolic reprogramming. The depletion of ITA in NEC correlates with an increased frequency of pro-inflammatory macrophage polarization, thereby exacerbating intestinal inflammatory injury. Importantly, our in vivo experiments revealed that treatment with 4-octyl itaconate (4OI) significantly mitigated intestinal symptoms associated with NEC in murine models. Mechanistic investigations showed that 4OI effectively suppressed M1 macrophage polarization by rescuing mitochondrial function and upregulating oxidative phosphorylation in macrophages.
Our results highlight ITA as a metabolic checkpoint of macrophage differentiation in NEC and suggest the therapeutic efficacy of 4OI in NEC.
Itaconate alleviates NEC by reprogramming M1 macrophage metabolism ACOD1 deficiency exacerbates NEC severity 4OI maintains intestinal barrier integrity. 4OI rescues NEC by regulating macrophage mitochondrial activity.
坏死性小肠结肠炎（NEC）是一种新生儿中迅速进展且严重的胃肠道疾病，其特征是由尚未完全理解的机制引发的炎症级联反应，导致肠道坏死和全身感染。本研究表明，衣康酸（ITA）通过调节巨噬细胞重编程在NEC中发挥保护作用。
使用免疫荧光染色和液相色谱 - 质谱法研究ITA表达的变化，并通过单细胞测序验证其对免疫细胞分化的影响。使用ACOD1和ACOD1LysM NEC小鼠模型进行体内实验。
我们在临床NEC样本中检测到ITA表达的变化，并证实了这些变化对免疫细胞分化的影响。体内实验证实了ITA在调节NEC中巨噬细胞分化的治疗作用，并且我们进一步研究了ITA调节巨噬细胞代谢重编程的机制。NEC中ITA的耗竭与促炎巨噬细胞极化频率增加相关，从而加剧肠道炎症损伤。重要的是，我们的体内实验表明，用4 - 辛基衣康酸（4OI）治疗可显著减轻小鼠模型中与NEC相关的肠道症状。机制研究表明，4OI通过挽救线粒体功能和上调巨噬细胞中的氧化磷酸化有效抑制M1巨噬细胞极化。
我们的结果突出了ITA作为NEC中巨噬细胞分化的代谢检查点，并表明4OI在NEC中的治疗效果。
衣康酸通过重编程M1巨噬细胞代谢减轻NEC；ACOD1缺乏加剧NEC严重程度；4OI维持肠道屏障完整性；4OI通过调节巨噬细胞线粒体活性挽救NEC。
