Wang Rong, Zhu Jianwei, Zhou Jinyi, Li Jinyang, Wang Min, Wu Yuqi, Zhao Danshan, Chen Xiancheng, Chen Xiaoyuan, Wang Yuetong, Zou Jianhua
Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, Jiangsu, 210046, China.
Hunan Provincial Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, Changsha Medical University, Changsha, Hunan, 410219, China.
Adv Sci (Weinh). 2025 Aug;12(30):e2503903. doi: 10.1002/advs.202503903. Epub 2025 Apr 29.
Ulcerative colitis (UC) is a chronic inflammatory bowel disease, characterized by focal iron overload. Herein, we reported that γ-glutamylcysteine (γGC) deletion in UC lesions intensified the disease by depleting intracellular GSH to induce macrophage ferroptosis, leading to macrophage M1 reprogramming and eventually exacerbating inflammation. To counteract this, the advanced microparticles (MPs)-based delivery system is selected to encapsulate γGC. The resulting γGC-MPs displayed the same porous and spiky morphology as their substrate's natural pollens, resulting in improved intestinal adhesion and enhanced lesion contact of γGC-MPs. Our results demonstrated that exogenous γGC supplementation could inhibit macrophage M1 polarization by restraining ferroptosis, as well as suppressing the PI3K/AKT pathway and TNF signaling pathway. Compared with free γGC, γGC-MPs significantly alleviated typical UC symptoms in dextran sulfate sodium (DSS)-induced colitis, evidenced by reduced intestinal inflammation, restored intestinal barrier function, and improved microbiota composition. Consequently, this study addressed critical gaps in understanding the causes of ferroptosis and its impact on macrophage reprogramming in UC, offering a novel synergistic therapeutic strategy for UC.
溃疡性结肠炎（UC）是一种慢性炎症性肠病，其特征为局部铁过载。在此，我们报告称，UC病变中γ-谷氨酰半胱氨酸（γGC）的缺失通过消耗细胞内谷胱甘肽（GSH）诱导巨噬细胞铁死亡，导致巨噬细胞M1重编程，最终加剧炎症，从而加重疾病。为了抵消这种情况，选择基于高级微粒（MPs）的递送系统来封装γGC。所得的γGC-MPs呈现出与其底物天然花粉相同多孔且带刺的形态，从而改善了肠道黏附并增强了γGC-MPs与病变部位的接触。我们的结果表明，外源性补充γGC可通过抑制铁死亡以及抑制PI3K/AKT途径和TNF信号通路来抑制巨噬细胞M1极化。与游离γGC相比，γGC-MPs显著减轻了葡聚糖硫酸钠（DSS）诱导的结肠炎中的典型UC症状，表现为肠道炎症减轻、肠道屏障功能恢复以及微生物群组成改善。因此，本研究填补了在理解UC中铁死亡原因及其对巨噬细胞重编程影响方面的关键空白，为UC提供了一种新的协同治疗策略。
