急性髓细胞白血病（AML）患者的预后仍较差，因为当前治疗方案无法完全根除导致疾病的白血病干细胞（LSCs）。先前的研究表明，氧化磷酸化（OXPHOS）是一种在LSCs中可作为靶点的必需过程。线粒体去乙酰化酶Sirtuin 3（SIRT3）在代谢调节中具有多方面的作用，已被证明能够调节癌症模型中的OXPHOS；但是，在LSCs的背景下尚未进行过研究。因此，我们试图确定SIRT3是否对LSC功能至关重要。使用RNAi和SIRT3抑制剂（YC8-02），我们证明SIRT3是人类原始LSC生存的关键靶点，但对于正常人类造血干细胞和祖细胞（HSPC）功能并不重要。为了阐明SIRT3在LSCs中必不可少的分子机制，我们结合了转录组学、蛋白质组学和脂质组学方法，显示SIRT3通过调节脂肪酸氧化（FAO）对LSC功能具有重要作用，这是需要支持人类LSC的氧化磷酸化和ATP产生的。此外，我们发现两种方法可以进一步增强对SIRT3抑制的LSCs的敏感性。首先，我们发现LSCs可以通过上调胆固醇酯化来耐受SIRT3抑制引起的脂肪酸累积的毒性效应。打破胆固醇平衡会使LSCs对YC8-02敏感，并增强LSC细胞死亡。其次，SIRT3抑制剂可以增强LSCs对BCL-2抑制剂venetoclax的敏感性。这些发现将SIRT3确立为脂质代谢的调节器和原始AML细胞的潜在治疗靶点。

Outcomes for patients with acute myeloid leukemia (AML) remain poor due to the inability of current therapeutic regimens to fully eradicate disease initiating leukemia stem cells (LSCs). Previous studies have demonstrated that oxidative phosphorylation (OXPHOS) is an essential process that is targetable in LSCs. Sirtuin 3 (SIRT3), a mitochondrial deacetylase with a multi-faceted role in metabolic regulation, has been shown to regulate OXPHOS in cancer models; however, it has not yet been studied in the context of LSCs. Thus, we sought to identify if SIRT3 is important for LSC function. Using RNAi and a SIRT3 inhibitor (YC8-02), we demonstrate that SIRT3 is a critical target for the survival of primary human LSCs but is not essential for normal human hematopoietic stem and progenitor cell (HSPC) function. To elucidate the molecular mechanisms by which SIRT3 is essential in LSCs we combined transcriptomic, proteomic, and lipidomic approaches, showing that SIRT3 is important for LSC function through the regulation of fatty acid oxidation (FAO) which is required to support oxidative phosphorylation and ATP production in human LSCs. Further, we discovered two approaches to further sensitize LSCs to SIRT3 inhibition. First, we found that LSCs tolerate the toxic effects of fatty acid accumulation induced by SIRT3 inhibition by upregulating cholesterol esterification. Disruption of cholesterol homeostasis sensitizes LSCs to YC8-02 and potentiates LSC cell death. Second, SIRT3 inhibition sensitizes LSCs to BCL-2 inhibitor venetoclax. Together, these findings establish SIRT3 as a regulator of lipid metabolism and potential therapeutic target in primitive AML cells.