High-fat diet-responsive DNM1 promotes hepatocellular carcinoma progression and predicts poor prognosis in viral-associated patients.

Abstract

Hepatocellular carcinoma (HCC) arises from diverse etiologies, among which metabolic dysfunction-associated liver disease and chronic viral hepatitis are the two major drivers worldwide. However, the molecular mechanisms linking metabolic stress to HCC progression remain incompletely understood. Dynamin-1 (DNM1), primarily known for its role in vesicular trafficking, has emerged as a potential oncogene, yet its prognostic and functional significance in HCC remains largely unexplored. Here, we investigated the role of DNM1 in high-fat diet (HFD)-associated hepatocarcinogenesis. Transcriptomic profiling was conducted to identify differentially expressed genes between normal and high-fat diet murine models, with human orthologs mapped. Clinical relevance was validated using The Cancer Genome Atlas (TCGA-LIHC) dataset. Survival analysis, GSEA (Gene Set Enrichment Analysis), and subgroup stratifications based on viral hepatitis status were performed. In vitro, loss-of-function assays (shRNA knockdown) were executed in HepG2 and SK-Hep1 cell lines to assess cell viability and migration. DNM1 was significantly upregulated in high-fat diet models. In the TCGA-LIHC cohort, high DNM1 expression was an independent risk factor for poor overall survival (HR=1.44, P=0.039) and correlated with advanced tumor stages (Stage III+IV, P=0.010). In vitro knockdown of DNM1 profoundly impaired cell proliferation and migration in HCC cell lines. Strikingly, DNM1 expression was further elevated in patients with concurrent viral hepatitis (P=0.009). GSEA revealed that high DNM1 expression was positively associated with viral infection pathways and negatively correlated with critical immune responses, including interferon-alpha/gamma responses and host immune cytolysis. Survival analysis stratified by four subgroups demonstrated that patients with both viral infection and high DNM1 expression exhibited the worst prognosis (Overall Log-rank P < 0.001). Our findings identify DNM1 as a high-fat diet-responsive regulator that links metabolic stress to hepatocellular carcinoma progression. Elevated DNM1 expression promotes malignant phenotypes in HCC and identifies a subgroup of viral-associated patients with particularly poor prognosis, highlighting DNM1 as a potential prognostic biomarker and therapeutic target.