Acyl-CoA synthetase short-chain family member 3 (ACSS3)

Acyl-CoA synthetase short-chain family member 3 (ACSS3) is a mitochondrial enzyme within the acyl-CoA synthetase family that catalyzes the activation of short-chain fatty acids—mainly propionate and acetate—into their respective CoA esters, such as propionyl-CoA and acetyl-CoA[1][5][6]. It plays a pivotal role in cellular energy metabolism, fatty acid processing, ketone body synthesis, and lipid homeostasis[1][3][5][6]. ACSS3 is especially enriched in metabolically active tissues, such as brown adipose tissue and liver, where it supports adaptation to fasting and ketogenic conditions, and it localizes to the mitochondrial inner membrane[3][4]. Experimental data show that ACSS3 can act as a gatekeeper of cancer progression, serving as a source for biosynthetic acetyl-CoA in tumor cells and being upregulated in gastric and other cancers[2][3]. In metabolic disease models, loss of ACSS3 disrupts propionate catabolism, leads to autophagy-driven adipose dysfunction, insulin resistance, and obesity, and pharmacologic inhibition of autophagy can partially rescue these effects[4]. ACSS3 expression or epigenetic regulation is emerging as a prognostic biomarker in several cancers and may represent a therapeutic target for metabolic and neoplastic diseases[2][3][4].

Other names

acyl-CoA synthetase short-chain family member 3, mitochondrialACSS3FLJ21963acetate--CoA ligase 3propionate--CoA ligaseAMP-binding enzyme33217

Inhibition of autophagy (pharmacologic intervention with hydroxychloroquine in metabolic syndrome models); Modulation of acetyl-CoA/propionyl-CoA supply, affecting lipid synthesis, histone acetylation, and cellular metabolism