脂肪酸合成酶（FASN）维持新生脂肪生成（DNL），以支持大多数增殖癌细胞的快速生长。脂原恶酰辅酶A（CoA）主要由碳水化合物产生，但也可由谷氨酰酸依赖的还原性羧化生成。在这里，我们显示在没有DNL的情况下，还原性羧化也会发生。在FASN缺陷细胞中，还原性羧化主要由异柠檬酸脱氢酶-1（IDH1）催化，但由IDH1生成的细胞质柠檬酸不被用于供应DNL。代谢流通分析（MFA）表明，FASN缺陷引起了胞质向粒线体的柠檬酸流通通量，通过粒线体柠檬酸转运蛋白（CTP）进行。此前，相似的途径已被证明可以缓解无附着生长的肿瘤球体中产生的氧化应激。我们进一步报道，肿瘤球体显示出降低的FASN活性，并且FASN缺陷细胞以CTP和IDH1依赖的方式获得对氧化应激的抵抗力。总之，这些数据表明，通过诱导胞质向粒线体的柠檬酸流通，无附着生长的恶性肿瘤细胞可以通过以FASN支持的快速生长来增加氧化还原能力。版权所有 © 2023 作者。由Elsevier Inc.出版。保留所有权利。

Fatty acid synthase (FASN) maintains de novo lipogenesis (DNL) to support rapid growth in most proliferating cancer cells. Lipogenic acetyl-coenzyme A (CoA) is primarily produced from carbohydrates but can arise from glutamine-dependent reductive carboxylation. Here, we show that reductive carboxylation also occurs in the absence of DNL. In FASN-deficient cells, reductive carboxylation is mainly catalyzed by isocitrate dehydrogenase-1 (IDH1), but IDH1-generated cytosolic citrate is not utilized for supplying DNL. Metabolic flux analysis (MFA) shows that FASN deficiency induces a net cytosol-to-mitochondria citrate flux through mitochondrial citrate transport protein (CTP). Previously, a similar pathway has been shown to mitigate detachment-induced oxidative stress in anchorage-independent tumor spheroids. We further report that tumor spheroids show reduced FASN activity and that FASN-deficient cells acquire resistance to oxidative stress in a CTP- and IDH1-dependent manner. Collectively, these data indicate that by inducing a cytosol-to-mitochondria citrate flux, anchorage-independent malignant cells can gain redox capacity by trading off FASN-supported rapid growth.Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.