2025年11月12日，西湖大学Z邹贻龙课题组在《自然》杂志发表论文，宣布他们探明了iPEX通过组织扩展实现微米分辨率的深空间蛋白质组学。

在这里，该研究团队通过扩展（iPEX）提出了原位成像蛋白质组学，它将各向同性组织放大与基质辅助激光解吸/电离（MALDI）质谱成像相结合。iPEX提供可扩展的空间分辨率到微米尺度，并大大提高了蛋白质鉴定的灵敏度10 - 100倍。iPEX以视网膜为模型，实现了高精度空间蛋白质组学图谱的构建、单细胞层和胞外结构的可视化以及共定位蛋白的鉴定。

iPEX适用于脑、肠、肝、类器官等多种组织，可在1 ~ 5 μm有效像素上检测600 ~ 1500种蛋白质。应用iPEX描绘5xFAD阿尔茨海默病小鼠大脑的空间蛋白质组学图谱，发现早发性线粒体异常。值得注意的是，在年轻小鼠中，过氧化物酶体乙酰辅酶A酰基转移酶ACAA1A（其中N392S突变体是阿尔茨海默病的单基因危险因素）下调。ACAA1缺失阻断了多种细胞环境下长链多不饱和脂肪酸（包括二十二碳六烯酸）的生物合成。这些脂质组改变在过表达野生型ACAA1而非ACAA1（N392S）的细胞中得以恢复，这表明长链多不饱和脂肪酸的失调在神经退行性变中具有早期作用。总之，这些结果表明，iPEX促进了非靶向空间蛋白质组学在微米分辨率的不同应用。

研究人员表示，正在开发的空间组学技术的数量正在增加。然而，一个缺失的工具是一种可以在高空间分辨率和覆盖范围下以非靶向方式定位组织中蛋白质的工具。

附：英文原文

Title: iPEX enables micrometre-resolution deep spatial proteomics via tissue expansion

Author: Wang, Fengxiang, Sun, Cuiji, Wu, Tianshu William, Fu, Yuting, Fan, Yujing, Zhao, Shuchang, Huang, Kaiyin, Pan, Zijian, Lu, Yang, Han, Jingrong Regina, Jia, Shikai, Zeng, Lizhou, Zhang, Sheng, Chen, Ting, An, Shaowei, Meng, Shuang Susie, Guo, Xun, Li, Weizhe, Lian, Heyuan, Sun, Xiaoting, Hu, Jin, Yang, Chuanzhen, Feng, Shan, Li, Pengfei, Du, Liyuan, Liu, Xiaodong, Piatkevich, Kiryl D., Zou, Yilong

Issue&Volume: 2025-11-12

Abstract: The number of spatial omics technologies being developed is increasing1. However, a missing tool is one that can locate proteins in tissues in an untargeted manner at high spatial resolution and coverage. Here we present in situ imaging proteomics via expansion (iPEX), which integrates isotropic tissue magnification2 with matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging. iPEX provides scalable spatial resolution down to the micrometre scale and substantially increases the sensitivity of protein identification by 10–100-fold. Using the retina as a model, iPEX enabled the construction of spatial proteomic maps with high precision, the visualization of single-cell layers and extrasomatic structures and the identification of colocalized proteins. iPEX was readily applied to diverse tissues, including brain, intestine, liver and organoids, detecting 600–1,500 proteins at 1–5-μm effective pixel size. The application of iPEX to depict spatial proteomic maps in brains of mice with 5xFAD Alzheimer’s disease revealed an early-onset mitochondrial aberrancy. Notably, in young mice, the peroxisomal acetyl-CoA acyltransferase ACAA1A—of which the N392S mutant is a monogenic risk factor in Alzheimer’s disease3—was downregulated. ACAA1 depletion blocked the biosynthesis of long-chain polyunsaturated fatty acids, including docosahexaenoic acid, in multiple cellular contexts. These lipidome alterations were restored in cells overexpressing wild-type ACAA1 but not ACAA1(N392S), which suggests that the dysregulation of long-chain polyunsaturated fatty acids has an early role in neurodegeneration. Together, these results demonstrate that iPEX facilitates untargeted spatial proteomics at micrometre resolution for diverse applications.

DOI: 10.1038/s41586-025-09734-0

Source: https://www.nature.com/articles/s41586-025-09734-0