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Urolithin D sensitizes hepatocellular carcinoma to T-cell responses through downregulating ACOT7/PD-L1 axis
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DOI：10.1016/j.lddd.2026.100334.png)
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Abstract
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Objective: The upregulation of programmed death-ligand 1 (PD-L1) is crucial for immune escape in hepatocellular carcinoma (HCC), but its related mechanisms and treatment strategies are not fully understood. This study focused on Acyl-CoA thioesterase 7 (ACOT7) and aimed to investigate how urolithins affect T-cell activity targeting HCC cells. Methods: ACOT7 expression patterns and their association with prognosis were analyzed using data from the TCGA-LIHC database. In vitro HCC models were established using HepG2 and Huh7 cells and treated with various concentrations of urolithins. A Transwell co-culture assay was used to analyze the interaction between HCC cells and T cells and to evaluate T-cell responses. Gene knockdown techniques were employed to explore the effect of ACOT7 on PD-L1 expression and cell proliferation. Results: Analysis of TCGA-LIHC data showed that ACOT7 was significantly overexpressed in HCC tumors and correlated with poor patient prognosis. ACOT7 expression was positively correlated with PD-L1 levels. In vitro experiments demonstrated that knockdown of ACOT7 inhibited HCC cell proliferation and enhanced their susceptibility to T cell-mediated attack by reducing PD-L1 expression. Among various urolithins, only urolithin D effectively inhibited the ACOT7/PD-L1 signaling axis. Treatment with urolithin D significantly increased the vulnerability of HCC cells to T-cell responses, as evidenced by decreased HCC cell viability, increased apoptosis, and enhanced production of immune-related cytokines by T cells. Conclusion: Urolithin D may inhibit HCC progression by promoting T-cell activity through suppression of the ACOT7/PD-L1 pathway. This finding suggests a potential novel therapeutic approach for HCC patients.
Keywords:
Liver cancer
Immune responses
Urolithins
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