ACOT7 fuels head and neck cancer growth by altering arachidonic acid and AKT-MDM2-p53 signaling

Scientists have identified acyl-CoA thioesterase 7 (ACOT7) as a driver of head and neck squamous cell carcinoma (HNSCC), a common malignancy with a poor clinical prognosis. In a study published in Cancer & Metabolism on 5 October 2026, Zhenning Jin, Jiayi Peng, Diana Messadi, Shun-Fa Yang, Shen Hu and colleagues report that ACOT7 is markedly elevated in HNSCC tumor tissues compared with adjacent normal tissues, and in HNSCC cell lines compared with normal human oral keratinocytes. Higher ACOT7 expression was associated with poorer survival not only in HNSCC but also in several other cancers, supporting its evaluation as a candidate prognostic biomarker.

ACOT7 belongs to a family of enzymes recognized as key regulators of lipid metabolism, yet their contributions to HNSCC pathogenesis had not been well understood. The enzyme is of particular interest because it catalyzes the hydrolysis of arachidonoyl-CoA to arachidonic acid, a lipid mediator known to promote tumor growth and signaling. To define its functional role, the team combined analysis of clinical datasets from TCGA and GEO with in vitro and in vivo experiments, manipulating ACOT7 expression through siRNA-mediated knockdown or lentiviral overexpression.

The functional assays showed that ACOT7 knockdown suppressed malignant phenotypes in vitro and tumor growth in vivo, whereas overexpression produced the opposite effects. Malignant phenotypes were assessed using MTT, invasion, migration, colony formation and tumor sphere assays, alongside tumor xenograft models. Metabolic measurements revealed that intracellular arachidonic acid levels, as well as arachidonic acid and prostaglandin E2 levels in tumor tissue, decreased after ACOT7 knockdown and increased after overexpression, linking the enzyme’s catalytic activity to changes in lipid mediators within tumors.

The researchers also probed how ACOT7 itself is regulated. Chromatin immunoprecipitation and inhibitor experiments supported the involvement of MYC in ACOT7 transcriptional regulation, suggesting that this oncogenic transcription factor may drive ACOT7 expression in HNSCC cells. Downstream of the enzyme, exogenous arachidonic acid enhanced colony formation and migration and increased total AKT abundance, while depletion of AKT reduced colony formation in the presence of arachidonic acid. These experiments connect the lipid product of ACOT7 to AKT-dependent growth behavior in cell models.

The study’s mechanistic findings center on the AKT-MDM2-p53 axis. ACOT7 knockdown reduced total AKT and p-MDM2 levels and increased p53 protein abundance, and depletion of AKT produced similar changes in p-MDM2 and p53. The authors conclude that ACOT7 promotes malignant phenotypes and alters arachidonic acid abundance in HNSCC, and that MYC-associated regulation together with changes in total AKT and p-MDM2 levels suggest a potential connection between ACOT7 and growth-related signaling. They emphasize that these findings support further evaluation of ACOT7 as a candidate therapeutic target.

Several caveats frame the results. The work is an early-access, peer-reviewed accepted article that remains subject to further edits before the final version of record. The mechanistic conclusions rest largely on cell-line experiments and xenograft models, and the authors describe the AKT-MDM2-p53 connection as a potential association rather than a fully established causal pathway. Even so, by tying a lipid-metabolism enzyme to both arachidonic acid availability and a key growth-signaling axis, the study offers a concrete starting point for testing whether ACOT7 levels could help stratify HNSCC patients by prognosis and whether targeting the enzyme or its downstream signaling could one day inform new therapeutic approaches for this difficult-to-treat cancer.

Subject of Research: The role of the lipid metabolism enzyme ACOT7 in head and neck squamous cell carcinoma progression

Article Title: ACOT7 promotes HNSCC progression by disrupting the AKT-MDM2-p53 axis

Article References: Jin, Z., Peng, J., Messadi, D., Yang, S.-F., & Hu, S. (2026). ACOT7 promotes HNSCC progression by disrupting the AKT-MDM2-p53 axis. Cancer & Metabolism. https://doi.org/10.1186/s40170-026-00459-w

Image Credits: AI Generated

DOI: 10.1186/s40170-026-00459-w

Keywords: ACOT7, head and neck squamous cell carcinoma, arachidonic acid, AKT-MDM2-p53 axis, lipid metabolism, MYC, prostaglandin E2, p53, prognostic biomarker, cancer metabolism, promotes, HNSCC