ACADS

ACADS Full Name

acyl-CoA dehydrogenase, C-2 to C-3 short chain; SCAD

ACADS Introduction

Short-chain acyl-CoA dehydrogenase (ACADS), commonly referred to as SCAD, is a critical mitochondrial matrix enzyme encoded by the ACADS gene. As a member of the acyl-CoA dehydrogenase family, it plays a foundational role in cellular lipid metabolism and energy production. The primary biological function of ACADS is to catalyze the initial step in the mitochondrial beta-oxidation spiral of short-chain fatty acids. Specifically, it acts upon fatty acids containing four to six carbon atoms, driving the dehydrogenation of substrates such as butyryl-CoA into crotonyl-CoA. Through this process, ACADS enables the continuous degradation of short-chain fatty acids into acetyl-CoA, which subsequently enters the tricarboxylic acid (TCA) cycle to generate ATP. This metabolic pathway is essential for maintaining systemic energy homeostasis, particularly during periods of fasting, intense cellular demand, or metabolic stress.

Figure 1. Bioinformatic analyses of ACADS-encoded proteins. (Source: Zhou W, et al. 2021)

Clinically, genetic dysregulation of this enzyme is traditionally associated with Short-Chain Acyl-CoA Dehydrogenase Deficiency (SCADD), an autosomal recessive inborn error of metabolism. SCADD is biochemically characterized by the abnormal accumulation of butyrylcarnitine in the blood and elevated ethylmalonic acid excretion in the urine. The clinical phenotype of SCADD is highly heterogeneous; while some pediatric patients may exhibit developmental delay, hypotonia, epilepsy, and hypoglycemia, a significant proportion of individuals identified through newborn screening remain completely asymptomatic throughout their lives. This broad phenotypic spectrum suggests that SCADD may often act as a susceptibility factor that requires additional environmental or genetic stressors to manifest clinically.

Beyond rare congenital metabolic disorders, recent research has highlighted ACADS as a highly relevant metabolic biomarker in oncology. Because cancer cells heavily rely on metabolic reprogramming to sustain rapid growth, the dysregulation of lipid metabolism enzymes is a common hallmark of malignancies. ACADS is frequently downregulated in solid tumors, such as hepatocellular carcinoma (HCC) and colorectal cancer. In these cancers, the loss of ACADS expression is often driven by promoter hypermethylation and is closely correlated with increased tumor proliferation, metastasis, and a poorer overall clinical prognosis. Furthermore, recent studies demonstrate that ACADS deficiency can alter the tumor immune microenvironment, inhibiting immunogenic cell death and suppressing antitumor immunity. Consequently, ACADS is emerging not only as a crucial metabolic regulator but also as a promising prognostic biomarker and potential therapeutic target.

Alternate Names for ACADS

ACADS; acyl-CoA dehydrogenase, C-2 to C-3 short chain; SCAD; ACAD3; short-chain specific acyl-CoA dehydrogenase, mitochondrial; butyryl-CoA dehydrogenase; unsaturated acyl-CoA reductase; short-chain acyl-CoA dehydrogenase; acyl-Coenzyme A dehydrogenase, C-2 to C-3 short chain; mitochondrial short-chain specific acyl-CoA dehydrogenase

• 1. Zhou W, et al. Quantification of Differential Metabolites in Dried Blood Spots Using Second-Tier Testing for SCADD/IBDD Disorders Based on Large-Scale Newborn Screening in a Chinese Population. Front Pediatr. 2021 Nov 19;9:757424.
  2. Yang F, et al. Short-chain acyl-CoA dehydrogenase initiates mtDNA demethylation and leakage to fuel antitumor immunity in colorectal cancer. Signal Transduct Target Ther. 2026 Mar 26;11(1):113.