D-xylose suppresses hepatocellular carcinoma progression by regulating dihydrodiol dehydrogenase and remodeling the immune microenvironment.

INTRODUCTION: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death with limited treatment options. Dihydrodiol dehydrogenase (DHDH), an enzyme involved in D-xylose metabolism, has unclear roles in tumorigenesis and immune regulation. This study aims to investigate the clinical significance, biological functions, and immunomodulatory mechanisms of DHDH in HCC, and to explore the therapeutic potential of targeting its metabolic activity. METHODS: DHDH expression and its clinical correlation were analyzed using TCGA-LIHC data and validated in HCC tissue microarrays. In vitro functional assays were performed using DHDH-overexpressing and knockdown Hepa1-6 cells. Immune interactions were assessed via co-culture with CD8(+) T cells and flow cytometry. Subcutaneous tumor models in immunodeficient and immunocompetent mice, alongside HCC organoid models, were used to evaluate tumor growth and immune microenvironment changes. The therapeutic effect of D-xylose, alone or combined with anti-PD-L1, was examined in vivo. RESULTS: DHDH was highly expressed in HCC tissues and significantly associated with poor prognosis. Functional studies demonstrated that DHDH overexpression promoted HCC cell proliferation and invasion while suppressing CD8(+) T cell activity, potentially through the upregulation of PD-L1 and downregulation of β2-microglobulin (B2M). Further investigations revealed that D-xylose, a metabolic substrate of DHDH, significantly enhanced intracellular NADPH production and reduced ROS levels, thereby alleviating oxidative stress-induced T cell dysfunction. In patient-derived organoid-PBMC co-culture models, D-xylose treatment markedly enhanced T cell immune activity. DISCUSSION: DHDH drives HCC progression and immune evasion by promoting an immunosuppressive microenvironment. Targeting DHDH with D-xylose restores CD8(+) T cell function and synergizes with immunotherapy.