The retinol-metabolizing enzyme DHRS3 coordinates antigen presentation, endothelial stability, and cholesterol metabolism to suppress hepatocellular carcinoma progression.

Hepatocellular carcinoma (HCC) remains a therapeutic challenge due to tumor microenvironment heterogeneity and metabolic reprogramming. Short-chain dehydrogenase/reductase 3, DHRS3, a retinol-metabolizing enzyme, exhibits paradoxical roles across cancers, but its specific function in HCC is poorly understood. This study integrated pan-cancer data from The Cancer Genome Atlas and genotype-tissue expression, conducted single-cell and spatial transcriptomic analyses, and carried out in vitro assays and in vivo xenograft models for validation. A machine learning framework was used to develop the DHRS3-cholesterol metabolic prognostic signature (DCMPS) by combining DHRS3 expression with cholesterol-related genes. DHRS3 was upregulated in HCC and associated with favorable prognosis. It enhanced antitumor immunity by promoting major histocompatibility complex class I/II antigen presentation and inhibited metastasis via SEMA4A signaling and endothelial-mesenchymal transition suppression. Conversely, DHRS3 drove proliferation through cholesterol metabolism, reversible by atorvastatin (ATO). ATO synergized with all-trans retinoic acid to suppress tumor growth and enhance immune cell infiltration. The DCMPS model outperformed Tumor Node Metastasis staging in prognostic prediction. DHRS3 acts as a dual-functional immune-metabolic regulator in HCC. The DCMPS signature serves as a robust prognostic biomarker and may guide the application of all-trans retinoic acid-ATO combination therapy, offering a rationale for a novel precision medicine strategy in HCC management.