代谢重塑是心脏衰竭的标志。癌症期间的肿瘤代谢应激增加了 ATP 依赖性柠檬酸裂解酶（ACL，Acly）的活性和丰度，从而促进组蛋白乙酰化和心脏适应。 ACL 对于脂质的从头合成至关重要，但这些代谢改变如何导致心脏结构和功能变化仍不清楚。我们使用了来自健康供体心脏和肥厚型心肌病患者的人类心脏组织样本。此外，我们使用 CRISPR/Cas9 基因编辑来灭活 MyH6-Cas9 小鼠心肌细胞中的 Acly。在体内，正电子发射断层扫描和离体稳定同位素示踪剂标记用于量化因 ACL 丢失而引起的代谢通量变化。我们使用 RNA 测序和基于质谱的代谢组学和蛋白质组学进行了多组学分析。使用代谢网络 CardioNet 将实验数据整合到计算模型中，以识别系统水平上显着失调的代谢过程。在这里，我们表明，在小鼠中，ACL 驱动心脏的代谢适应，以维持收缩功能、组蛋白乙酰化和脂质调节。值得注意的是，我们发现 ACL 的丧失会增加葡萄糖氧化，同时维持脂肪酸氧化。离体同位素示踪实验显示，葡萄糖衍生的柠檬酸盐从线粒体进入细胞质的流出减少，证实柠檬酸盐是心脏还原代谢所必需的。我们证明 YAP 失活会促进 ACL 缺陷。计算通量分析和综合多组学分析表明，ACL 丢失会诱导替代异柠檬酸脱氢酶 1 通量进行补偿。这项研究从机制上描述了心脏代谢如何补偿因 ACL 丢失而受到抑制的柠檬酸代谢，并揭示了心脏的代谢脆弱性。

Metabolic remodeling is a hallmark of the failing heart. Oncometabolic stress during cancer increases the activity and abundance of the ATP-dependent citrate lyase (ACL, Acly ), which promotes histone acetylation and cardiac adaptation. ACL is critical for the de novo synthesis of lipids, but how these metabolic alterations contribute to cardiac structural and functional changes remains unclear.We utilized human heart tissue samples from healthy donor hearts and patients with hypertrophic cardiomyopathy. Further, we used CRISPR/Cas9 gene editing to inactivate Acly in cardiomyocytes of MyH6-Cas9 mice. In vivo, positron emission tomography and ex vivo stable isotope tracer labeling were used to quantify metabolic flux changes in response to the loss of ACL. We conducted a multi-omics analysis using RNA-sequencing and mass spectrometry-based metabolomics and proteomics. Experimental data were integrated into computational modeling using the metabolic network CardioNet to identify significantly dysregulated metabolic processes at a systems level.Here, we show that in mice, ACL drives metabolic adaptation in the heart to sustain contractile function, histone acetylation, and lipid modulation. Notably, we show that loss of ACL increases glucose oxidation while maintaining fatty acid oxidation. Ex vivo isotope tracing experiments revealed a reduced efflux of glucose-derived citrate from the mitochondria into the cytosol, confirming that citrate is required for reductive metabolism in the heart. We demonstrate that YAP inactivation facilitates ACL deficiency. Computational flux analysis and integrative multi-omics analysis indicate that loss of ACL induces alternative isocitrate dehydrogenase 1 flux to compensate.This study mechanistically delineates how cardiac metabolism compensates for suppressed citrate metabolism in response to ACL loss and uncovers metabolic vulnerabilities in the heart.