他莫昔芬是雌激素受体阳性（ER  ）亚型乳腺癌患者的一线治疗药物，该亚型乳腺癌患者占乳腺癌总发病率的 70-80%。然而，临床上对他莫昔芬的耐药性已变得越来越普遍，这突出表明需要确定潜在的细胞机制。在我们的研究中，我们采用了基因组规模的 CRISPR-Cas9 功能丧失筛选和验证实验，发现 Tafazzin (TAZ)（一种线粒体转酰基酶）对于维持 ER 乳腺癌细胞对他莫昔芬和其他药物的细胞敏感性至关重要。化疗。从机制上讲，我们发现心磷脂的合成和成熟依赖于 TAZ，是维持细胞对他莫昔芬的敏感性所必需的。 TAZ 代谢酶活性的丧失会导致 ERα 下调和治疗抵抗。有趣的是，我们观察到 TAZ 缺乏还会导致溶血磷脂酰胆碱 (LPC) 上调，进而抑制 ERα 表达和核定位，从而导致他莫昔芬耐药。 LPC 进一步代谢为溶血磷脂酸 (LPA)，这是一种支持细胞存活的生物活性分子。因此，我们的研究结果表明，TAZ 的消耗通过 LPC-LPA 磷脂合成轴促进他莫昔芬耐药，而针对这一脂质代谢途径可以恢复细胞对他莫昔芬治疗的敏感性。© 2023。作者，获得 Springer 独家许可自然美国公司

Tamoxifen is the frontline therapeutic agent for the estrogen receptor-positive (ER + ) subtype of breast cancer patients, which accounts for 70-80% of total breast cancer incidents. However, clinical resistance to tamoxifen has become increasingly common, highlighting the need to identify the underlying cellular mechanisms. In our study, we employed a genome-scale CRISPR-Cas9 loss-of-function screen and validation experiments to discover that Tafazzin (TAZ), a mitochondrial transacylase, is crucial for maintaining the cellular sensitivity of ER+ breast cancer cells to tamoxifen and other chemotherapies. Mechanistically, we found that cardiolipin, whose synthesis and maturation rely on TAZ, is required to maintain cellular sensitivity to tamoxifen. Loss of metabolic enzymatic activity of TAZ causes ERα downregulation and therapy resistance. Interestingly, we observed that TAZ deficiency also led to the upregulation of lysophosphatidylcholine (LPC), which in turn suppressed ERα expression and nuclear localization, thereby contributing to tamoxifen resistance. LPC is further metabolized to lysophosphatidic acid (LPA), a bioactive molecule that supports cell survival. Thus, our findings suggest that the depletion of TAZ promotes tamoxifen resistance through an LPC-LPA phospholipid synthesis axis, and targeting this lipid metabolic pathway could restore cell susceptibility to tamoxifen treatment.© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.