| 2017 |
ACSS3 (rat ortholog) was demonstrated by molecular cloning and recombinant protein expression to be a propionyl-CoA synthetase localized to the mitochondrial matrix, preferentially utilizing propionate as a substrate with a KM of 0.19 mM. Knockdown of acss3 in HepG2 cells significantly decreased propionyl-CoA synthetase activity in cell lysates, and ACSS3 levels/activity were upregulated in liver mitochondria during fasting. |
Molecular cloning, recombinant protein purification from E. coli, in vitro enzymatic assay with substrate specificity profiling, subcellular fractionation of liver tissue, siRNA knockdown with enzymatic activity readout |
Journal of biochemistry |
High |
28003429
|
| 2022 |
ACSS3 is the key enzyme for propionate catabolism in brown adipose tissue, located on the mitochondrial inner membrane. Knockout of Acss3 in mice reduces brown adipose tissue (BAT) mass, increases white adipose tissue (WAT) mass, leads to glucose intolerance and insulin resistance exacerbated by high-fat diet, and elevates propionate levels in BAT and serum. Elevated propionate drives adipocyte autophagy, and pharmacological inhibition of autophagy with hydroxychloroquine ameliorates obesity and insulin resistance in Acss3-/- mice. |
Acss3 knockout mouse model, metabolic phenotyping (glucose tolerance test, insulin tolerance test), propionate measurement in BAT and serum, pharmacological autophagy inhibition with hydroxychloroquine, cultured brown/white adipocyte propionate treatment with autophagy readout |
Clinical and translational medicine |
High |
35184387
|
| 2024 |
RPN11 deubiquitinates and stabilizes METTL3, which enhances m6A modification and expression of ACSS3. ACSS3 in turn generates propionyl-CoA that upregulates lipid metabolism genes via histone propionylation. This RPN11-METTL3-ACSS3-histone propionylation pathway is activated in livers of NAFLD patients, and hepatocyte-specific RPN11 knockout protects mice from diet-induced liver steatosis. |
Hepatocyte-specific RPN11 knockout mice, diet-induced NAFLD model, mechanistic epistasis linking RPN11-METTL3-ACSS3, histone propionylation assay, human NAFLD liver samples |
Cell metabolism |
High |
39146936
|
| 2021 |
ACSS3 represses prostate cancer progression by reducing lipid droplet (LD) deposits through regulating the stability of the LD coat protein perilipin 3 (PLIN3). Restoration of ACSS3 expression in PCa cells reduces LD deposits, promotes apoptosis by increasing endoplasmic reticulum (ER) stress, decreases de novo intratumoral androgen synthesis, and reverses enzalutamide resistance. Loss of ACSS3 expression in PCa is associated with gene promoter methylation. |
Co-IP, qRT-PCR, Western blotting, LC/MS lipid profiling, Oil Red O assay, TG and cholesterol measurement, Bisulfite genomic sequencing PCR and MSP for promoter methylation, CCK-8 and Transwell functional assays, xenograft tumorigenesis model in vivo |
Theranostics |
Medium |
33391508
|
| 2023 |
ACSS3 participates in lipid and carbohydrate metabolic homeostasis in alveolar epithelial cells: overexpression downregulates CPT-1A (reducing fatty acid oxidation) and leads to lipid droplet accumulation, while enhancing glycolysis and extracellular lactic acid. ACSS3 increases succinyl-CoA production through propionic acid metabolism and decreases acetyl-CoA and ATP generation. Overexpression of Acss3 in vivo inhibited ECM deposition and attenuated ground-glass opacity in bleomycin-induced pulmonary fibrosis. |
Proteomic analysis of IPF patient and bleomycin-mouse samples, ACSS3 overexpression in A549 cells with metabolite measurements (succinyl-CoA, acetyl-CoA, ATP, lactic acid), CPT-1A protein measurement, lipid droplet staining, in vivo bleomycin fibrosis model with micro-CT |
Biochimica et biophysica acta. Molecular basis of disease |
Medium |
37979225
|
| 2020 |
ACSS3 is responsible for lipogenic acetyl-CoA synthesis from acetate in bladder urothelial carcinoma (BLCA) cells under metabolic stress, is required for acetate utilization and histone acetylation, and promotes BLCA cell growth. |
Isotope tracing for lipogenic acetyl-CoA generation, ACSS3 knockdown with acetate utilization and histone acetylation readouts, cell growth assays |
Oncogenesis |
Medium |
32398651
|
| 2025 |
ACSS3 knockdown in NSCLC cells promotes ferroptosis through transcriptional activation of the p53 pathway, which suppresses the SLC7A11/GPX4 axis. ACSS3 loss enhances p53 stability, and ACSS3 promotes tumor growth by inhibiting p53-mediated ferroptosis. ACSS3 knockdown led to mitochondrial contraction, increased ROS, and decreased mitochondrial membrane potential in NSCLC cells. |
ACSS3 knockdown and overexpression in NSCLC cells, in vitro and in vivo tumor growth assays, ferroptosis markers (SLC7A11, GPX4, ROS), p53 stability assessment, mitochondrial morphology/function measurements |
Experimental cell research |
Medium |
39961466
|
| 2025 |
BCL11A transcriptionally represses ACSS3 as a direct target gene. BCL11A deficiency increases ACSS3 expression, promoting autophagosome formation and enhanced autophagy flux, which reduces DNA damage and ROS under UVB irradiation, protecting epidermal cells from UVB-induced death. This protective effect was blocked by pharmacological inhibition of autophagy or BCL11A overexpression. |
CRISPR/Cas9-mediated BCL11A deletion, ACSS3 identified as direct transcriptional target, autophagy flux assays, ROS measurement, DNA damage assays, pharmacological autophagy inhibition rescue |
Communications biology |
Medium |
41039024
|
| 2025 |
ACSS3 modulates aerobic glycolysis and keloid fibroblast (KF) activity via the Wnt/β-Catenin pathway. Lentiviral overexpression of ACSS3 in KFs suppressed their activity, normalized glycolytic flux, and reduced levels of critical glycolytic enzymes, while ACSS3 knockdown had opposite effects that were reversed by the Wnt/β-Catenin inhibitor ICG-001. |
Lentiviral ACSS3 overexpression and knockdown in keloid fibroblasts, glycolytic flux measurement, glycolytic enzyme levels, pharmacological rescue with ICG-001 (Wnt/β-Catenin inhibitor), single-cell analysis |
Cellular signalling |
Low |
40783148
|
| 2023 |
The EGFR/AKT pathway upregulates ACSS3 expression in glioblastoma (GBM) cells in an NF-κB-dependent manner, contributing to lipid remodeling and energy metabolism reprogramming in EGFR-activated GBM. |
Single-cell RNA sequencing and untargeted metabolomics of clinical GBM, EGFR/AKT pathway inhibition with MK-2206, NF-κB-dependent regulation of ACSS3 expression assessed in GBM cells, intracranial tumor model in vivo |
Cancer communications (London, England) |
Low |
37920878
|
| 2024 |
ACSS3 functions as an acetyltransferase (or donor for acetyltransferase activity) contributing to CBP/p300-mediated acetylation of Sox2 at K75 in colorectal cancer cells, as identified by LC-MS-based proteomics binding partner analysis. |
LC-MS-based proteomics to identify binding partners of Sox2 in CRC cell lines, identification of ACSS3 as involved in K75 acetylation of Sox2 along with CBP/p300 |
Cancers |
Low |
38473392
|