Shen Leiting, Chen Jiayu, Tou Jinfa
Department of Neonatal Surgery, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China.
Cell Death Discov. 2025 Aug 5;11(1):365. doi: 10.1038/s41420-025-02665-9.
Neonatal necrotizing enterocolitis (NEC) is a severe gut disease primarily affecting preterm infants, driven significantly by inflammatory macrophages. This study combined bioinformatics (single-cell/tissue RNA sequencing) and experiments to identify key macrophage changes in NEC. Analysis revealed substantial macrophage infiltration in NEC tissues. These macrophages were highly inflammatory and strongly linked to cell death pathways (ferroptosis, pyroptosis, apoptosis), with scores significantly higher than controls and correlating with inflammation. In vitro, LPS-stimulated inflammatory macrophages showed elevated ferroptosis, evidenced by cell rupture, death, increased ACSL4, decreased GPX4, iron overload, lipid peroxidation, and heightened cytokine release. Critically, the ferroptosis inhibitor Ferrostatin-1 (Fer-1) reversed these effects. While LPS alone didn't kill intestinal epithelial cells, supernatant from LPS-stimulated macrophages significantly increased intestinal epithelial cell death. Fer-1 inhibition of macrophage ferroptosis prevented this epithelial damage. In vivo, a mouse NEC model (induced by hypersomolar feeding, hypoxia, cold) displayed macrophage infiltration, inflammation, and elevated ferroptosis markers. Intraperitoneal Fer-1 administration improved intestinal injury in NEC mice. This study demonstrates that macrophage ferroptosis is a critical driver of NEC inflammation and tissue damage. Inhibiting ferroptosis with Fer-1 effectively reduces both macrophage death and subsequent intestinal epithelial injury, mitigating NEC progression. These findings highlight macrophage ferroptosis as a key therapeutic target for NEC, offering a foundation for new treatment strategies.
新生儿坏死性小肠结肠炎（NEC）是一种主要影响早产儿的严重肠道疾病，炎症巨噬细胞在其中起了重要推动作用。本研究结合生物信息学（单细胞/组织RNA测序）和实验，以确定NEC中巨噬细胞的关键变化。分析显示NEC组织中有大量巨噬细胞浸润。这些巨噬细胞具有高度炎症性，且与细胞死亡途径（铁死亡、焦亡、凋亡）密切相关，其评分显著高于对照组，且与炎症相关。在体外，脂多糖（LPS）刺激的炎症巨噬细胞显示铁死亡增加，表现为细胞破裂、死亡、ACSL4增加、GPX4减少、铁过载、脂质过氧化以及细胞因子释放增加。关键的是，铁死亡抑制剂Ferrostatin-1（Fer-1）可逆转这些效应。虽然单独的LPS不会杀死肠道上皮细胞，但LPS刺激的巨噬细胞的上清液显著增加了肠道上皮细胞死亡。Fer-1抑制巨噬细胞铁死亡可防止这种上皮损伤。在体内，小鼠NEC模型（由高渗喂养、缺氧、寒冷诱导）表现出巨噬细胞浸润、炎症以及铁死亡标志物升高。腹腔注射Fer-1可改善NEC小鼠的肠道损伤。本研究表明巨噬细胞铁死亡是NEC炎症和组织损伤的关键驱动因素。用Fer-1抑制铁死亡可有效减少巨噬细胞死亡及随后的肠道上皮损伤，减轻NEC的进展。这些发现突出了巨噬细胞铁死亡作为NEC关键治疗靶点的地位，为新的治疗策略奠定了基础。
