ZCCHC4 Orchestrates Hepatocellular Carcinoma Metastasis by Regulating Lipid biosynthesis and TMEM97/LCN2/Twist1 Pathway.

Metastasis remains a major therapeutic challenge in hepatocellular carcinoma (HCC), yet its underlying molecular mechanisms are not fully understood. This study reveals that ZCCHC4 acts as a key promoter of HCC metastasis. We demonstrate that ZCCHC4 enhances the metastatic capacity of HCC cells both in vitro and in vivo. Mechanistically, ZCCHC4 upregulates key lipid biosynthesis enzymes (HMGCR, SQLE, FASN, and SCD), leading to intracellular accumulation of cholesterol and fatty acids which drive metastasis. Concurrently, ZCCHC4 transcriptionally activates TMEM97, thereby augmenting Wnt signaling. Furthermore, TMEM97 interacts with LCN2 to retain it in the cytoplasm. This sequestration relieves LCN2-mediated inhibition of the transcription factor Twist1, consequently promoting epithelial-mesenchymal transition (EMT) and metastasis. Consistent with these findings, ZCCHC4 level positively correlates with levels of TMEM97 and the lipid enzymes in clinical HCC specimens, and high ZCCHC4 expression is associated with poor patient prognosis. In summary, our work identifies ZCCHC4 as a critical metastasis driver via coordinated regulation of lipid metabolism and the TMEM97/LCN2/Twist1 axis, presenting novel potential targets for treating HCC metastasis.