Lenvatinib resistance significantly limits its clinical efficacy and application in the treatment of hepatocellular carcinoma (HCC). Mitofusin 2 (MFN2) is an important GTPase involved in mitochondrial fusion, energy balance and mitophagy. The role and regulatory mechanism of MFN2 in HCC progression and lenvatinib resistance remain unclear. Herein, we demonstrated that the family with sequence similarity 111 member B (FAM111B) regulated the stability of MFN2 and the sensitivity to lenvatinib in HCC. Mechanistically, FAM111B promoted MFN2 ubiquitination by recruiting RAN-binding protein 9 (RANBP9), a core subunit of the C-terminal to LisH (CTLH) E3 ligase complex. Targeting FAM111B generated hyperfused mitochondria, driving a metabolic shift from glycolysis to oxidative phosphorylation (OXPHOS) and antagonising cytoprotective mitophagy. Clinically, FAM111B protein levels were inversely correlated with MFN2 expression in HCC samples, with patients who exhibited high FAM111B levels having a worse prognosis and reduced sensitivity to lenvatinib treatment. More importantly, we developed glypican-3 (GPC3)-targeted lipid nanoparticles for efficient delivery of siFAM111B, which demonstrated strong efficacy in combination with lenvatinib. Together, our findings uncover a novel regulatory mechanism for MFN2 posttranscriptional regulation and highlight the therapeutic potential of targeting FAM111B in HCC treatment.