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SETDB1 decline promotes the resistance to sorafenib via DRP1 phosphorylation-mediated mitochondrial dysfunction in

Mingjian Fan1, Jiahang Wu1, Yunjiao Wu2

  • 1KingMed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou 511436, China.

Biochemical and Biophysical Research Communications
|May 9, 2025
PubMed

Insights

Hepatic SETDB1 expression improves sorafenib efficacy in hepatocellular carcinoma (HCC) by preventing mitochondrial dysfunction and excessive DRP1 phosphorylation. SETDB1 may serve as a predictive biomarker for sorafenib therapy in HCC patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Sorafenib is a standard treatment for advanced hepatocellular carcinoma (HCC).
  • Individualized resistance to sorafenib remains a significant clinical challenge.
  • The role of histone H3K9 methyltransferase SETDB1 in sorafenib resistance is largely unknown.

Purpose of the Study:

  • To investigate the role of SETDB1 in modulating sorafenib sensitivity in HCC.
  • To elucidate the underlying molecular mechanisms involving mitochondrial function and DRP1 phosphorylation.

Main Methods:

  • Analysis of SETDB1 expression in TCGA-LIHC and clinical HCC samples.
  • Assessment of sorafenib cytotoxicity in SETDB1-silenced hepatoma cells.
  • Evaluation of mitochondrial function (membrane potential, mSOX, mtDNA content, fission) and DRP1 phosphorylation (pDRP1S616) in HepG2 cells.
  • Correlation analysis between hepatic pDRP1S616 levels and patient prognosis.

Main Results:

  • Hepatic SETDB1 expression positively correlates with better prognosis in HCC patients treated with sorafenib.
  • SETDB1 silencing diminishes sorafenib's cytotoxic effects and impairs mitochondrial function.
  • SETDB1 knockdown increases mitochondrial superoxide (mSOX), reduces mitochondrial DNA (mtDNA) content, and promotes DRP1S616 phosphorylation.
  • Inhibition of DRP1 phosphorylation (pDRP1S616A) enhances sorafenib sensitivity, mSOX, and mtDNA content.
  • Elevated hepatic pDRP1S616 levels negatively correlate with prognosis in sorafenib-treated HCC patients.

Conclusions:

  • SETDB1 enhances sorafenib susceptibility in HCC by maintaining mitochondrial integrity and regulating DRP1 phosphorylation.
  • Hepatic SETDB1 expression is a potential predictive biomarker for sorafenib therapy in HCC.
  • Targeting SETDB1 or modulating mitochondrial function could offer new therapeutic strategies for overcoming sorafenib resistance.
Keywords:
DRP1Hepatocellular carcinomaMitochondriaSETDB1Sorafenib

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