机化性肺炎（OP）是间质性肺炎中最常见和致命的疾病之一，与肺癌一样。脂质代谢的重编程是许多疾病的新标志，包括癌症、心血管疾病以及肝纤维化和硬化。由鞘氨醇和脂肪酸组成的神经酰胺水平升高与急性和慢性肺部疾病的发展有关。然而，它们在 OP 中的病理生理学意义尚不清楚。本研究的目的是调查脂质代谢重编程在 OP 中的作用，重点关注炎症和纤维化。综合多组学分析方法，包括单细胞 RNA 测序、Visium CytAssist 空间转录组学、蛋白质组学、代谢组学和质谱分析，用于分析组织。利用OP小鼠模型，对巨噬细胞中的分子机制进行研究。结果显示OP与脂质代谢重编程之间存在显着关联，其特征是与脂质代谢相关的多个基因的异常表达，其中CD36、SCD1和CES1主要在巨噬细胞中表达异常。肺泡巨噬细胞中 CD36 缺乏，导致线粒体中积累的 C16/24 神经酰胺表达增加，导致线粒体自噬或线粒体功能障碍。 OP中肺泡巨噬细胞的数量显着减少，这可能是由于OP中涉及GSH/SLC3A2/GPX4的铁死亡信号通路通过CD36下调所致。此外，巨噬细胞分泌的DPP7和FABP4影响上皮细胞纤维化。CD36通过调节脂质代谢，抑制OP组织肺泡巨噬细胞中涉及SLC3A2/GPX4的铁死亡途径，从而代表了CD36介导的新的抗铁死亡和抗纤维化作用。至少部分是由神经酰胺引起的。我们的研究结果揭示了机化性肺炎与脂质代谢重编程之间的显着关联，并将为理解患者机化性肺炎的机制做出重大贡献。© 2024 作者。约翰·威利出版的《临床与转化医学》

Organising pneumonia (OP) is one of the most common and lethal diseases in the category of interstitial pneumonia, along with lung cancer. Reprogramming of lipid metabolism is a newly recognized hallmark of many diseases including cancer, cardiovascular disorders, as well as liver fibrosis and sclerosis. Increased levels of ceramides composed of sphingosine and fatty acid, are implicated in the development of both acute and chronic lung diseases. However, their pathophysiological significance in OP is unclear. The aim of this study was to investigate the role of lipid metabolism reprogramming in OP, focusing on inflammation and fibrosis.Comprehensive multi-omics profiling approaches, including single-cell RNA sequencing, Visium CytAssist spatial transcriptomics, proteomics, metabolomics and mass spectrometry, were employed to analyze the tissues. OP mice model was utilized and molecular mechanisms were investigated in macrophages.The results revealed a significant association between OP and lipid metabolism reprogramming, characterized by an abnormal expression of several genes related to lipid metabolism, including CD36, SCD1, and CES1 mainly in macrophages. CD36 deficiency in alveolar macrophages, led to an increased expression of C16/24 ceramides that accumulated in mitochondria, resulting in mitophagy or mitochondrial dysfunction. The number of alveolar macrophages in OP was significantly reduced, which was probably due to the ferroptosis signaling pathway involving GSH/SLC3A2/GPX4 through CD36 downregulation in OP. Furthermore, macrophage secretion of DPP7 and FABP4 influenced epithelial cell fibrosis.CD36 inhibited the ferroptosis pathway involving SLC3A2/GPX4 in alveolar macrophages of OP tissue by regulating lipid metabolism, thus representing a new anti-ferroptosis and anti-fibrosis effect of CD36 mediated, at least in part, by ceramides.Our findings reveal a significant association between organising pneumonia and lipid metabolism reprogramming and will make a substantial contribution to the understanding of the mechanism of organising pneumonia in patients.© 2024 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.