Objective <p>Mitochondrial fission regulator 2 (MTFR2) is upregulated in multiple cancers, including hepatocellular carcinoma (HCC); however, its mechanistic role in HCC progression remains poorly understood.</p> Methods <p>MTFR2 expression in HCC tissues was analyzed using TCGA and GEO databases. Validation of MTFR2 expression levels in clinical samples and HCC cell lines was performed through qRT-PCR and western blot. Functional effects of MTFR2 overexpression and knockdown on HCC cell proliferation, migration, and invasion were assessed via CCK-8, colony formation, wound healing, and transwell assays. In vivo tumor growth was evaluated in xenograft mouse models.</p> Results <p>MTFR2 was significantly overexpressed in HCC tissues and cell lines. Enhanced proliferation, migration, invasion, and colony formation were observed in MTFR2-overexpressing HCC cells, whereas knockdown of MTFR2 suppressed these malignant phenotypes. Mechanistic studies demonstrated that MTFR2 promotes proliferation, migration, and invasion of HCC cells via the PI3K/AKT signaling pathway. Additionally, MTFR2 knockdown significantly attenuated tumor growth in xenograft models.</p> Conclusion <p>These findings demonstrate that MTFR2 promotes HCC progression via modulation of the PI3K/AKT pathway, underscoring its potential as a therapeutic target for HCC.</p>