代谢重编程是癌症的一个标志，其特征是高度依赖糖酵解和加强利用乙酸作为替代碳源。 ACSS2是乙酸盐代谢的关键调节因子，在各种恶性肿瘤的发生和进展中发挥着重要作用。 ACSS2 促进乙酸盐转化为乙酰辅酶A，乙酰辅酶A参与多种代谢途径，并作为蛋白质乙酰化的表观遗传调节因子，从而调节自噬等关键细胞过程。然而，ACSS2、糖酵解、蛋白乙酰化和自噬在卵巢癌（OC）中的作用和内在联系仍有待阐明。利用临床标本和在线数据库，我们分析了 OC 中 ACSS2 的表达及其与临床预后的关系。通过敲低 ACSS2，我们评估了它对恶性表型、乙酸代谢、糖酵解和自噬的影响。使用海马测定、透射电子显微镜、膜电位测量和稳定同位素标记技术全面分析 OC 细胞的代谢变化。切

Metabolic reprogramming is a hallmark of cancer, characterized by a high dependence on glycolysis and an enhanced utilization of acetate as an alternative carbon source. ACSS2 is a critical regulator of acetate metabolism, playing a significant role in the development and progression of various malignancies. ACSS2 facilitates the conversion of acetate to acetyl-CoA, which participates in multiple metabolic pathways and functions as an epigenetic regulator of protein acetylation, thereby modulating key cellular processes such as autophagy. However, the roles and intrinsic connections of ACSS2, glycolysis, protein acetylation, and autophagy in ovarian cancer (OC) remain to be elucidated.Utilizing clinical specimens and online databases, we analysed the expression of ACSS2 in OC and its relationship with clinical prognosis. By knocking down ACSS2, we evaluated its effects on the malignant phenotype, acetate metabolism, glycolysis, and autophagy. The metabolic alterations in OC cells were comprehensively analysed using Seahorse assays, transmission electron microscopy, membrane potential measurements, and stable-isotope labeling techniques. CUT&TAG and co-immunoprecipitation techniques were employed to explore the deacetylation of autophagy-related proteins mediated by ACSS2 via SIRT1. Additionally, through molecular docking, transcriptome sequencing, and metabolomics analyses, we validated the pharmacological effects of paeonol on ACSS2 and the glycolytic process in OC cells. Finally, both in vitro and in vivo experiments were performed to investigate the impact of paeonol on autophagy and its anti-OC effects mediated through the ACSS2/SIRT1 deacetylation axis.ACSS2 is significantly upregulated in OC and is associated with poor prognosis. Knockdown of ACSS2 inhibits OC cells proliferation, migration, invasion, angiogenesis, and platinum resistance, while reducing tumour burden in vivo. Mechanistically, inhibiting ACSS2 reduces acetate metabolism and suppresses glycolysis by targeting HXK2. This glycolytic reduction promotes the translocation of ACSS2 from the cytoplasm to the nucleus, leading to increased expression of the deacetylase SIRT1. SIRT1 mediates the deacetylation of autophagy-related proteins, such as ATG5 and ATG2B, thereby significantly activating autophagy in OC cells and exerting antitumor effects. Paeonol inhibits acetate metabolism and glycolysis in OC cells by targeting ACSS2. Paeonol activates autophagy through the ACSS2/SIRT1/ATG5/ATG2B deacetylation axis, demonstrating inhibition of OC in vitro and in vivo.Pae can serve as an effective, low-toxicity, multi-targeted drug targeting ACSS2 and glycolysis. It activates autophagy through the ACSS2/SIRT1/ATG5/ATG2B deacetylation signalling cascade, thereby exerting anti-OC effects. Our study provides new insights into the malignant mechanisms of OC and offers a novel strategy for its treatment.Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.