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Updated: Jun 27, 2026

A Syngeneic Orthotopic Osteosarcoma Sprague Dawley Rat Model with Amputation to Control Metastasis Rate
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A Syngeneic Orthotopic Osteosarcoma Sprague Dawley Rat Model with Amputation to Control Metastasis Rate

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C/EBP alpha agonist ICCB280 overcomes doxorubicin resistance in osteosarcoma through mitochondrial dynamics-dependent

Yuchen Han1,2, Hui Li3, Chunyuan Xue4

  • 1Senior Department of Pediatrics, The Seventh Medical Center, Chinese PLA General Hospital, Beijing, China.

Cell Death & Disease
|June 25, 2026
PubMed

Insights

Doxorubicin resistance in osteosarcoma (OS) is a major challenge. New strategies targeting mitochondrial dynamics and reactive oxygen species (ROS) show promise in overcoming this resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Doxorubicin (DOX) resistance is a significant barrier to effective osteosarcoma (OS) treatment.
  • Mitochondrial dynamics and reactive oxygen species (ROS) accumulation are key factors in DOX-induced cell death.
  • Understanding novel targets for combating DOX resistance in OS is crucial.

Purpose of the Study:

  • To investigate the C/EBPα/GREM1/p-ERK signaling pathway's role in sensitizing OS to DOX.
  • To explore the potential of targeting mitochondrial homeostasis and DOX-induced cell death for therapeutic benefit.
  • To evaluate pharmacological agents that can overcome DOX resistance in OS.

Main Methods:

  • Investigated the C/EBPα/GREM1/p-ERK signaling pathway in OS cells.
  • Utilized C/EBPα agonist ICCB280 and ERK pathway inhibitor PD98059.
  • Assessed the effects of these agents on DOX sensitivity in vitro and in vivo models.

Main Results:

  • The C/EBPα/GREM1/p-ERK pathway sensitizes OS to DOX by promoting mitochondrial fission and ROS-induced apoptosis.
  • ICCB280 and PD98059 individually augmented DOX sensitivity in OS.
  • Combined administration of ICCB280 and PD98059 synergistically enhanced DOX's cytotoxic effect.

Conclusions:

  • Co-administration of ICCB280 and PD98059 counteracts doxorubicin resistance in osteosarcoma.
  • This combination intensifies GREM1 activation and inhibits ERK phosphorylation, suppressing OPA1 expression.
  • The strategy promotes mitochondrial fission, effectively overcoming chemotherapy resistance in OS.

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