ACAA2

ACAA2 Full Name

acetyl-CoA acyltransferase 2

ACAA2 Introduction

Acetyl-CoA acyltransferase 2 (ACAA2), also known as mitochondrial 3-oxoacyl-CoA thiolase, is a pivotal metabolic enzyme central to cellular energy homeostasis. Its primary function is to catalyze the final, rate-limiting step of the mitochondrial fatty acid beta-oxidation spiral. During this critical metabolic process, ACAA2 facilitates the cleavage of 3-ketoacyl-CoA to generate acyl-CoA and acetyl-CoA. By driving lipid metabolism, ACAA2 ensures a steady supply of acetyl-CoA for the tricarboxylic acid (TCA) cycle, making it essential for energy production, lipid homeostasis, and the regulation of cellular apoptosis.

In recent years, the dysregulation of ACAA2 has been closely linked to a variety of human diseases, particularly metabolic disorders and various malignancies. Because of its central role in lipid metabolism—a pathway often hijacked by rapidly proliferating cells—ACAA2 exhibits complex, context-dependent functions in cancer. For example, in hepatocellular carcinoma (HCC), ACAA2 is frequently downregulated, and its deficiency is associated with tumor progression, increased metastasis, and the formation of an immunosuppressive tumor microenvironment. Conversely, in other cancer types, it functions as an oncogene or diagnostic marker. Recent studies highlight that elevated ACAA2 expression serves as a novel molecular indicator for highly aggressive cancers with a neuroendocrine phenotype, such as small cell lung cancer and neuroendocrine prostate cancer. Furthermore, it has been shown to promote tumor growth and invasion in human ovarian cancer via specific signaling pathways and glycosylation modifications.

Figure 1. Long chain fatty acid activation, entry into mitochondria and metabolism via fatty acid oxidation. (Source: Dunning KR, et al. 2014)

Beyond oncology, ACAA2 is increasingly recognized for its role in systemic metabolic and fibrotic diseases. For instance, modifications of ACAA2, such as palmitoylation, have been found to induce ferroptosis in hepatic stellate cells, thereby driving liver fibrosis in metabolic dysfunction-associated steatotic liver disease (MASLD). Additionally, ACAA2 has demonstrated a protective role against lipid peroxidation and cardiac dysfunction in the context of renal insufficiency. As our understanding of metabolic reprogramming expands, ACAA2 stands out not only as a critical regulator of cellular metabolism but also as a promising prognostic biomarker and therapeutic target for treating both metabolic diseases and cancer.

Alternate Names for ACAA2

ACAA2; acetyl-CoA acyltransferase 2; acetyl Coenzyme A acyltransferase 2; 3-ketoacyl-CoA thiolase, mitochondrial; DSAEC; mitochondrial 3 oxoacyl Coenzyme A thiolase; T1; beta ketothiolase; beta-ketothiolase; acetyl-Coenzyme A acyltransferase 2

• 1. Dunning KR, et al. Regulation of fatty acid oxidation in mouse cumulus-oocyte complexes during maturation and modulation by PPAR agonists. PLoS One. 2014 Feb 5;9(2):e87327.
  2. Wu D, et al. Downregulated Acetyl-CoA Acyltransferase 2 Promoted the Progression of Hepatocellular Carcinoma and Participated in the Formation of Immunosuppressive Microenvironment. J Hepatocell Carcinoma. 2023 Aug 9;10:1327-1339.