Acetyl-CoA synthetase 2 contributes to a better prognosis for liver cancer by switching acetate-glucose metabolism

Sep 22, 2026

Acetyl-CoA synthetase 2 (ACSS2)-dependent acetate use is linked to tumorigenesis under nutrient-poor conditions, yet liver metabolism differs from other organs. This study comprehensively examined ACSS2 roles in liver cancer and acetate metabolism across in vitro, in vivo, and human settings. ACSS2 expression decreased in patients, and PET-CT showed lower-grade cells preferred 11C-acetate, whereas higher-grade behavior reversed. High-ACSS2 cells avidly absorbed acetate in glucose-sufficient conditions, and isotope tracing indicated more acetate incorporation, stronger lipid anabolism, and reduced malignancy. ACSS2 downregulation increased tumor occurrence in vivo, and low-ACSS2 cohorts showed reduced anabolism, elevated glycolysis/hypoxia, and poorer prognosis.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages13

Reading Time33 min

AccessFree to download

Introduction

Acetate and ACSS2 in cancer metabolism

Controversies in acetate uptake and malignancy

Rationale for studying liver cancer

[www.nature.com/emm](www.nature.com/emm) ARTICLE OPEN Acetyl-CoA synthetase 2 contributes to a better prognosis for liver cancer by switching acetate-glucose metabolism Kyung Hee Jung 1,5 ✉, Sujin Lee2,5, Han Sun Kim2,5, Jin-Mo Kim2,5, Yun Ji Lee 1, Min Seok Park1, Myeong-Seong Seo1, Misu Lee3, Mijin Yun4 ✉, Sunghyouk Park2 ✉ and Soon-Sun Hong 1 ✉ © The Author(s) 2024 | | Acetyl-CoA synthetase 2 (ACSS2)-dependent acetate usage has generally been associated with tumorigenesis and increased malignancy in cancers under nutrient-depleted conditions. However, the nutrient usage and metabolic characteristics of the liver differ from those of other organs; therefore, the mechanism of ACSS2-mediated acetate metabolism may also differ in liver cancer. To elucidate the underlying mechanisms of ACSS2 in liver cancer and acetate metabolism, the relationships between patient acetate uptake and metabolic characteristics and between ACSS2 and tumor malignancies were comprehensively studied in vitro, in vivo and in humans. Clinically, we initially found that ACSS2 expression was decreased in liver cancer patients. Moreover, PET-CT imaging conﬁrmed that lower-grade cancer cells take up more 11C-acetate but less 18F-ﬂuorodeoxyglucose (18F-FDG); however, this trend was reversed in higher-grade cancer. Among liver cancer cells, those with high ACSS2 expression avidly absorbed acetate even in a glucose-sufﬁcient environment, whereas those with low ACSS2 expression did not, thereby showing correlations with their respective ACSS2 expression. Metabolomic isotope tracing in vitro and in vivo revealed greater acetate incorporation, greater lipid anabolic metabolism, and less malignancy in high-ACSS2 tumors. Notably, ACSS2 downregulation in liver cancer cells was associated with increased tumor occurrence in vivo. In human patient cohorts, patients in the low-ACSS2 subgroup exhibited reduced anabolism, increased glycolysis/hypoxia, and poorer prognosis. We demonstrated that acetate uptake by ACSS2 in liver cancer is independent of glucose depletion and contributes to lipid anabolic metabolism and reduced malignancy, thereby leading | | | --- | --- | --- | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | to a better prognosis for liver cancer patients. | | | | | Experimental & Molecular Medicine (2024) 56:721–733; [https://doi.org/10.1038/s12276-024-01](https://doi.org/10.1038/s12276-024-01)185-3 | | | | | | INTRODUCTION Glucose is considered the preferred nutrient for cancer cells according to Otto Warburg’s proposal of aerobic glycolytic properties for all growing cancer cells1. However, other nutrients, such as glutamine, lactate, and acetate, can also be utilized by tumors under certain environmental conditions2–4. Acetate usage depends on acetyl-CoA synthetase 2 (ACSS2); speciﬁcally, the use of acetate in cancers seems to occur mostly under nutrientdepleted or hypoxic conditions4–6. Another aspect of acetate uptake is its relationship with tumor malignancy. A higher level of ACSS2 is associated with a shorter survival time and metastasis inpatients with brain, breast, or prostate cancers7,8. Bioinformatic analyses have suggested links between increased acetate utilization and higher malignancy under hypoxic conditions9, 10. Although the above studies suggest that hypoxia/nutrient depletion is positively correlated with cancer and that hypoxia/ nutrient depletion and higher acetate uptake are positively correlated with cancer malignancy, there is contrasting evidence. It has been established that a high glucose uptake, which might limit acetate uptake, can be induced under hypoxic conditions via hypoxia-inducible factors associated with increased cancer malignancy11, 12. Acetate metabolism through ACSS2 seems tobe important in leukemogenesis, although blood cancer cells are exposed to nutrient- and oxygen-rich environments13. P

FAQs

How is ACSS2 expression related to liver cancer patients’ outcomes?

ACSS2 expression was decreased in liver cancer patients, and the low-ACSS2 subgroup showed reduced anabolism, increased glycolysis/hypoxia, and poorer prognosis.

What did PET-CT imaging reveal about acetate versus glucose use across cancer grades?

Lower-grade cancer cells took up more 11C-acetate but less 18F-FDG, while this pattern reversed in higher-grade cancer cells.

Why does the study emphasize ACSS2-driven acetate metabolism in a glucose-sufficient environment?

High-ACSS2 liver cancer cells absorbed acetate even when glucose was sufficient, linking ACSS2 expression with acetate uptake and metabolic characteristics associated with reduced malignancy.

Sep 22, 2026

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