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Targeting FAM111B attenuates mitophagy and increases the sensitivity to lenvatinib treatment by increasing MFN2

Yu-Chuan Yan1,2, Li-Juan Shao3, Guang-Xiao Meng1,4

  • 1Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China.

Cell Death & Disease
|August 25, 2025
PubMed

Insights

Family with sequence similarity 111 member B (FAM111B) regulates Mitofusin 2 (MFN2) stability, impacting hepatocellular carcinoma (HCC) sensitivity to lenvatinib. Targeting FAM111B with GPC3-targeted nanoparticles offers a promising therapeutic strategy for HCC.

Area of Science:

  • Mitochondrial biology
  • Cancer research
  • Drug resistance mechanisms

Background:

  • Lenvatinib resistance is a major challenge in hepatocellular carcinoma (HCC) treatment.
  • Mitofusin 2 (MFN2), a GTPase regulating mitochondrial dynamics, has an unclear role in HCC progression and lenvatinib resistance.

Purpose of the Study:

  • To elucidate the role and regulatory mechanism of family with sequence similarity 111 member B (FAM111B) in HCC progression and lenvatinib resistance.
  • To investigate FAM111B's impact on Mitofusin 2 (MFN2) stability and sensitivity to lenvatinib.

Main Methods:

  • Investigated FAM111B's role in promoting MFN2 ubiquitination via recruitment of RAN-binding protein 9 (RANBP9) and the CTLH E3 ligase complex.
  • Analyzed the effects of targeting FAM111B on mitochondrial fusion, metabolic shift (glycolysis to oxidative phosphorylation), and mitophagy.
  • Correlated FAM111B and MFN2 protein levels with clinical outcomes and lenvatinib sensitivity in HCC patient samples.
  • Developed and tested glypican-3 (GPC3)-targeted lipid nanoparticles for siFAM111B delivery in combination therapy.

Main Results:

  • FAM111B promotes MFN2 ubiquitination and degradation, leading to altered mitochondrial dynamics and metabolism.
  • Targeting FAM111B induces mitochondrial hyperfusion, shifts metabolism to oxidative phosphorylation, and inhibits cytoprotective mitophagy.
  • High FAM111B levels correlate with decreased MFN2 expression, poorer prognosis, and reduced lenvatinib sensitivity in HCC patients.
  • GPC3-targeted nanoparticles delivering siFAM111B combined with lenvatinib showed significant efficacy.

Conclusions:

  • FAM111B is a novel regulator of MFN2 stability and a key determinant of lenvatinib sensitivity in HCC.
  • Targeting FAM111B represents a potential therapeutic strategy to overcome lenvatinib resistance in HCC.
  • Combined therapy using GPC3-targeted siFAM111B delivery and lenvatinib demonstrates therapeutic promise for HCC treatment.

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