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NCAPG confers ferroptosis resistance of hepatocellular carcinoma through NSUN2-mediated m5C modification

Zhihao Huang1, Jiakun Wang1, Aoxiao He2

  • 1Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330000, China.

Cellular Signalling
|November 19, 2025
PubMed

Insights

Non-SMC condensin I complex subunit G (NCAPG) promotes hepatocellular carcinoma (HCC) resistance to ferroptosis by stabilizing GPX4 expression. Targeting NCAPG may enhance ferroptosis-based cancer therapies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Ferroptosis is a promising hepatocellular carcinoma (HCC) treatment strategy, but clinical applications are limited by poor understanding of its upstream mechanisms and biomarkers.
  • Non-SMC condensin I complex subunit G (NCAPG) is an oncogene in HCC, but its role in ferroptosis remains unexplored.

Purpose of the Study:

  • To investigate the role of NCAPG in ferroptosis resistance in HCC.
  • To elucidate the molecular mechanisms by which NCAPG influences ferroptosis in HCC.

Main Methods:

  • In vivo and in vitro experiments were conducted to assess ferroptosis resistance.
  • Protein-protein interaction assays were used to identify interactions between NCAPG and NSUN2.
  • mRNA stability assays and m5C modification analysis were performed to study GPX4 regulation.

Main Results:

  • NCAPG was found to promote ferroptosis resistance in HCC cells, both in vivo and in vitro.
  • NCAPG regulates GPX4 expression at both mRNA and protein levels, conferring resistance to ferroptosis.
  • NCAPG interacts with NSUN2, inhibiting its degradation and promoting GPX4 mRNA stability via m5C modification, thereby enhancing ferroptosis resistance.

Conclusions:

  • NCAPG protects HCC cells from ferroptosis by upregulating GPX4 expression in a NSUN2-dependent manner.
  • NCAPG represents a potential therapeutic target for improving ferroptosis-based treatments in HCC.
  • Understanding NCAPG's role in ferroptosis resistance can guide the development of novel anti-cancer therapies for HCC.
Keywords:
FerroptosisHepatocellular carcinomaPost-transcriptional modificationProtein-protein interactionm5C modification

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