Metabolic Enzyme BCAT1 Drives Endometriosis Cell Growth Through Histone Acetylation

Endometriosis remains one of the most stubborn conditions in gynecology: surgery can remove lesions, but the disease often comes back, and hormonal therapies bring side effects that many patients cannot tolerate long term. Now a research team in Ningbo, China, reports that an enzyme better known for breaking down branched-chain amino acids may be a driving force behind the disease’s cellular behavior. In a study published in Frontiers in Genetics, the group found that branched-chain amino acid transaminase 1, or BCAT1, is markedly elevated in endometriosis tissue and appears to fuel the proliferation, migration and invasion of ectopic endometrial stromal cells by reshaping fatty acid metabolism and boosting the expression of a key metabolic enzyme called ACLY.

The team, led by Liang Chen of the Department of Gynecology at The Affiliated Women and Children’s Hospital of Ningbo University, began with tissue from 30 patients with endometriosis and 30 controls without the disease. Using quantitative reverse transcription polymerase chain reaction and Western blotting, they measured BCAT1 levels in ectopic endometriotic lesions, in paired eutopic endometrium from the uterine cavity of the same patients, and in normal endometrial tissue from the control group. BCAT1 expression was significantly increased in the endometriosis samples. The researchers then cross-checked the finding against a publicly available gene expression dataset, GSE120103, and again saw significantly higher BCAT1 in endometriosis tissue. Receiver operating characteristic analysis suggested that BCAT1 levels could distinguish endometriosis tissue from normal controls with high sensitivity, although the authors themselves describe that analysis as exploratory.

BCAT1 is a cytosolic enzyme that catalyzes the first step in the degradation of the branched-chain amino acids leucine, isoleucine and valine, converting them into their corresponding branched-chain alpha-keto acids. It has attracted attention in cancer research because it is highly expressed in several tumor types and promotes cell proliferation; overexpressing it enhances the growth, migration and invasion of nasopharyngeal carcinoma cells, for example. But its role in endometriosis, a benign yet invasive gynecological condition affecting roughly ten percent of women of reproductive age, had never been reported. The Ningbo team also found BCAT1 significantly elevated in primary ectopic endometrial stromal cells, or EESCs, isolated from patient lesions, compared with normal endometrial stromal cells.

To probe what BCAT1 actually does in these cells, the researchers used two independent small interfering RNAs to knock down BCAT1 in EESCs and, in parallel, constructed cells overexpressing the enzyme. The results were consistent across assays. CCK-8 proliferation tests showed that BCAT1 knockdown inhibited EESC proliferation while overexpression promoted it, and colony formation assays told the same story. Wound healing experiments, in which cell proliferation was suppressed with mitomycin C so that measured closure reflected genuine migration, showed that reducing BCAT1 slowed the migration rate of the cells, while boosting it accelerated closure. Transwell assays, with and without Matrigel coating, revealed that BCAT1 knockdown significantly decreased both invasive and migratory capacity, whereas overexpression enhanced both. Rescue experiments strengthened the case for specificity: when the team re-expressed BCAT1 in knockdown cells, proliferation and migration recovered. Western blotting added a molecular signature, showing that BCAT1 knockdown upregulated E-cadherin and downregulated N-cadherin, changes associated with reduced cell motility, with overexpression producing the opposite pattern.

The most striking part of the study concerns metabolism. Transcriptomic sequencing of EESCs with and without BCAT1 knockdown revealed thousands of differentially expressed genes, and KEGG pathway enrichment pointed to significant alterations in fatty acid biosynthesis. After BCAT1 knockdown, fatty acid biosynthesis-related genes were downregulated to varying degrees, with ACLY, ATP-citrate lyase, showing a particularly marked decrease. Functional metabolic readouts followed the same direction: knocking down BCAT1 reduced the oxygen consumption rate of the cells, lowered lipid droplet content measured by BODIPY staining, and decreased total cholesterol and triglyceride levels, while overexpressing BCAT1 raised all of these parameters. In short, BCAT1 appears to push these cells into a more lipid-building, more energy-consuming state.

ACLY is a logical link in that chain. The enzyme converts citrate and coenzyme A into acetyl-CoA and oxaloacetate, and acetyl-CoA is the essential building block for de novo lipogenesis as well as the substrate for acetylation modifications on proteins. The researchers confirmed by qRT-PCR and Western blotting that BCAT1 knockdown significantly reduced ACLY expression in EESCs, while BCAT1 overexpression upregulated it. They also found ACLY significantly elevated in endometriosis tissues, mirroring the pattern seen for BCAT1, and Spearman correlation analysis showed a positive relationship between the two enzymes’ expression levels.

To test whether ACLY is functionally required for BCAT1’s effects, the team ran rescue experiments using SB-204990, a potent ACLY inhibitor, at a concentration of 10 micromolar determined from an IC50 curve, and separately with siRNA-mediated ACLY knockdown. BCAT1 overexpression promoted proliferation and colony formation in EESCs, but ACLY inhibition markedly attenuated that pro-proliferative effect. Inhibiting ACLY likewise suppressed BCAT1’s ability to drive migration and invasion, and it blunted the increases in lipid accumulation, oxygen consumption, cholesterol and triglycerides that BCAT1 overexpression normally produces. The authors conclude that BCAT1 promotes EESC proliferation by upregulating ACLY expression and enhancing lipid accumulation.

The mechanistic twist is epigenetic. Because acetyl-CoA feeds histone acetylation, the researchers measured acetyl-CoA and acetylated histone H3 levels in the cells. BCAT1 knockdown significantly decreased both. Leucine treatment raised acetyl-CoA and Ac-H3 levels, but BCAT1 knockdown blunted that increase, and sodium acetate, which raises histone acetylation, partially restored ACLY expression and Ac-H3 levels in BCAT1-knockdown cells. Chromatin immunoprecipitation followed by quantitative PCR showed that BCAT1 knockdown significantly decreased acetylation levels in the ACLY promoter region itself. Finally, C646, a selective competitive inhibitor of the p300/CBP histone acetyltransferases, blocked the upregulation of ACLY and the H3K27ac mark induced by BCAT1 overexpression. Together, these experiments support a model in which BCAT1 sustains acetyl-CoA production, which drives histone acetylation at the ACLY promoter, which in turn maintains ACLY expression and lipid synthesis.

The authors are candid about the limits of the work. All mechanistic experiments were performed in vitro, without animal models, and cell culture cannot reproduce the hormonal regulation, immune microenvironment and inflammatory conditions of endometriosis in the body. The clinical cohort was a single-center retrospective series of 30 cases per group, so multicenter validation is needed. No stable isotope metabolic tracing was used, so there is no direct kinetic evidence of fatty acid synthesis rates, and the intervention substrates sodium acetate and leucine have broad metabolic effects that complicate interpretation. The ACLY inhibitor SB-204990 also carries potential off-target risks. The team proposes BCAT1 as a potential therapeutic target and calls for in vivo studies, including murine endometriosis models, to test whether the BCAT1-ACLY-H3K27ac axis holds up in living systems and whether drugs targeting it could ever be safe and effective.

Subject of Research: The role of BCAT1 in fatty acid metabolism, ACLY expression and histone acetylation in endometriosis cells

Article Title: BCAT1 promotes acetylation of ACLY through fatty acid metabolism pathway promoting the occurrence and development of endometriosis

Article References: Xu, Y., Shen, Y., Yan, Y., & Chen, L. (2026). BCAT1 promotes acetylation of ACLY through fatty acid metabolism pathway promoting the occurrence and development of endometriosis. Frontiers in Genetics, 17, Article 1818692. https://doi.org/10.3389/fgene.2026.1818692

Image Credits: AI Generated

DOI: 10.3389/fgene.2026.1818692

Keywords: endometriosis, BCAT1, ACLY, fatty acid metabolism, histone acetylation, ectopic endometrial stromal cells, epigenetics, acetyl-CoA, in vitro study, gynecology, metabolic reprogramming, Frontiers in Genetics