Integrative multi-omics profiling reveals DRG1 promotes hepatocellular carcinoma via c-Myc phosphorylation and facilitates lenvatinib resistance.
BACKGROUND & AIMS Developmentally regulated GTP-binding protein 1 (DRG1), a member of the GTPase family, has been implicated in cancer progression; however, its biological function and therapeutic relevance in hepatocellular carcinoma (HCC) remain poorly understood. This study aimed to define the role of DRG1 in HCC progression and uncover its underlying regulatory mechanisms. METHODS Multi-omics analyses, clinical tissue validation, in vitro functional assays, and in vivo xenograft models were integrated to investigate the biological function, regulatory mechanism, and therapeutic relevance of DRG1 in HCC. RESULTS DRG1 was significantly upregulated in HCC tissues and associated with aggressive clinicopathological characteristics and poor patient survival. Integrated single-cell and spatial transcriptomic analyses revealed preferential DRG1 expression in malignant regions and its association with an immunosuppressive tumor microenvironment. Mechanistically, DRG1 promoted HCC cell proliferation through regulation of c-Myc activation, while HDAC2 was identified as an upstream regulator of DRG1 expression. Furthermore, DRG1 depletion enhanced sensitivity to lenvatinib treatment in HCC models. CONCLUSIONS Our findings identify DRG1 as a potential prognostic biomarker and therapeutic target in HCC. The HDAC2-DRG1-c-Myc regulatory network contributes to malignant progression, while DRG1 inhibition represents a potential strategy to improve lenvatinib response.