Bis(monoacylglycero)phosphates (BMPs)，一类高度丰富于内溶酶体器官内的脂质，是激活鞘脂类分解酶的溶酶体内隔囊关键成分。尽管相对于其他磷脂，BMPs尚未受到足够的研究，但最近的报告将BMPs的失调与包括神经退行性疾病和溶酶体贮积性疾病在内的各种病理状态联系起来。由于细胞转化所特有的显著溶酶体重构可能会影响BMP的丰度和功能，因此我们采用非定向脂质组学方法，在几种乳腺癌体外和体内模型以及对比非转化细胞和组织中，鉴定和定量BMP物种。我们发现，在转化细胞中的BMP水平相对于正常细胞较低，并且人类和小鼠乳腺肿瘤模型中均存在22:6脂肪酸基链含有的BMP物种的一致富集。我们的功能分析指出一个工作模型，即22:6 BMPs在肿瘤细胞中充当响应性氧化物清除剂，保护溶酶体免受氧化剂诱导的溶酶体膜通透性的影响。我们的发现表明，乳腺肿瘤细胞可能将多不饱和脂肪酸转化成BMP脂质，作为对抗升高的响应性氧化物水平保护其溶酶体的适应性反应，并提出BMP介导的溶酶体保护是一种肿瘤特异性漏洞，可以在治疗方面加以利用。版权所有©2023，由Elsevier BV出版。

Bis(monoacylglycero)phosphates (BMPs), a class of lipids highly enriched within endolysosomal organelles, are key components of the lysosomal intraluminal vesicles responsible for activating sphingolipid catabolic enzymes. While BMPs are understudied relative to other phospholipids, recent reports associate BMP dysregulation with a variety of pathological states including neurodegenerative diseases and lysosomal storage disorders. Since the dramatic lysosomal remodeling characteristic of cellular transformation could impact BMP abundance and function, we employed untargeted lipidomics approaches to identify and quantify BMP species in several in vitro and in vivo models of breast cancer and comparative non-transformed cells and tissues. We observed lower BMP levels within transformed cells relative to normal cells, and consistent enrichment of docosahexaenoic acid (22:6) fatty acyl chain-containing BMP species in both human- and mouse-derived mammary tumorigenesis models. Our functional analysis points to a working model whereby 22:6 BMPs serve as reactive oxygen species scavengers in tumor cells, protecting lysosomes from oxidant-induced lysosomal membrane permeabilization. Our findings suggest that breast tumor cells might divert polyunsaturated fatty acids into BMP lipids as part of an adaptive response to protect their lysosomes from elevated reactive oxygen species levels, and raise the possibility that BMP-mediated lysosomal protection is a tumor-specific vulnerability that may be exploited therapeutically.Copyright © 2023. Published by Elsevier B.V.