This study investigates the role of mitochondrial dynamics, particularly mitochondrial fission, in the progression of hepatocellular carcinoma (HCC). The authors used gene expression data from the MitoCarta 3.0 database and The Cancer Genome Atlas (TCGA) to identify mitochondrial dynamic genes. They performed consensus clustering based on the expression of these genes, dividing patients into two clusters. Cluster 2, characterized by heightened mitochondrial fission, showed a worse prognosis. A ten-gene prognostic signature was constructed using univariate COX regression and LASSO regression, with all ten genes being up-regulated in the high-risk group. The signature was validated through various analyses, including immune infiltration, tumor mutational burden (TMB), tumor stemness indices (TSI), and response to immune checkpoint blockade (ICB) therapy. The study found that the high-risk group had a higher mutation frequency of TP53, increased immune checkpoint expression, a higher TSI score, and a lower TIDE score. Transmission electron microscopy (TEM), hematoxylin-eosin (H&E) staining, immunohistochemistry (IHC), western blotting (WB), and immunofluorescence (IF) were used to visualize mitochondrial morphology and protein expression. The results suggest that MTFR2-dependent mitochondrial fission promotes HCC progression and could serve as a therapeutic target.This study investigates the role of mitochondrial dynamics, particularly mitochondrial fission, in the progression of hepatocellular carcinoma (HCC). The authors used gene expression data from the MitoCarta 3.0 database and The Cancer Genome Atlas (TCGA) to identify mitochondrial dynamic genes. They performed consensus clustering based on the expression of these genes, dividing patients into two clusters. Cluster 2, characterized by heightened mitochondrial fission, showed a worse prognosis. A ten-gene prognostic signature was constructed using univariate COX regression and LASSO regression, with all ten genes being up-regulated in the high-risk group. The signature was validated through various analyses, including immune infiltration, tumor mutational burden (TMB), tumor stemness indices (TSI), and response to immune checkpoint blockade (ICB) therapy. The study found that the high-risk group had a higher mutation frequency of TP53, increased immune checkpoint expression, a higher TSI score, and a lower TIDE score. Transmission electron microscopy (TEM), hematoxylin-eosin (H&E) staining, immunohistochemistry (IHC), western blotting (WB), and immunofluorescence (IF) were used to visualize mitochondrial morphology and protein expression. The results suggest that MTFR2-dependent mitochondrial fission promotes HCC progression and could serve as a therapeutic target.