我们之前已经证明胰腺癌干细胞 (PaCSC) 对线粒体氧化磷酸化 (OXPHOS) 的显着依赖，这使得能够利用多种底物，包括脂肪酸 (FA)。值得注意的是，脂质清除失调和异常的 FA 代谢与 PDAC 进展有关。我们的生物信息学分析显示，与正常组织样本相比，PDAC 组织样本中脂质代谢相关基因的表达升高，这与干性特征相关。此外，与分化后代相比，PaCSC 表现出多种脂质代谢基因的表达增强和脂滴积累增加。棕榈酸、油酸和亚麻酸 FA 治疗显着增强了 CD133 PaCSC 的自我更新和化疗耐药性。相反，FA 摄取、储存和代谢的抑制剂在体外和体内均减少了 CSC 数量。从机制上讲，抑制 FA 代谢会抑制 OXPHOS 活性，导致 PaCSC 能量消耗和随后的细胞死亡。重要的是，将FAO抑制剂和吉西他滨治疗相结合可增强体外和体内的药物疗效，有效减少CSC的含量和功能。以FAO抑制剂为目标是针对这种高致瘤性人群的一种有前途的治疗策略。©2024。作者。

We have previously demonstrated the significant reliance of pancreatic Cancer Stem Cells (PaCSCs) on mitochondrial oxidative phosphorylation (OXPHOS), which enables versatile substrate utilization, including fatty acids (FAs). Notably, dysregulated lipid scavenging and aberrant FA metabolism are implicated in PDAC progression.Our bioinformatics analyses revealed elevated expression of lipid metabolism-related genes in PDAC tissue samples compared to normal tissue samples, which correlated with a stemness signature. Additionally, PaCSCs exhibited heightened expression of diverse lipid metabolism genes and increased lipid droplet accumulation compared to differentiated progenies. Treatment with palmitic, oleic, and linolenic FAs notably augmented the self-renewal and chemotherapy resistance of CD133+ PaCSCs. Conversely, inhibitors of FA uptake, storage and metabolism reduced CSC populations both in vitro and in vivo. Mechanistically, inhibition of FA metabolism suppressed OXPHOS activity, inducing energy depletion and subsequent cell death in PaCSCs. Importantly, combining a FAO inhibitor and Gemcitabine treatment enhanced drug efficacy in vitro and in vivo, effectively diminishing the CSC content and functionality.Targeting FAO inhibition represents a promising therapeutic strategy against this highly tumorigenic population.© 2024. The Author(s).