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Morusin targeting GDF15 enhances ferroptosis and overcomes cisplatin resistance in NSCLC

Liang Zhang1, Huan Liu2, Si Jiang2

  • 1Department of Respiratory and Critical Care Medicine, Yantaishan Hospital Affiliated to Binzhou Medical University, Binzhou Medical University, Yantai, Shandong, China.

Frontiers in Pharmacology
|July 6, 2026
PubMed
Abstract

Insights

Morusin (Mor) enhances cisplatin (DDP) sensitivity in non-small cell lung cancer (NSCLC) by promoting GDF15 degradation and inducing ferroptosis. This suggests Mor-based combination therapy is a promising treatment strategy for NSCLC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Morusin (Mor) is a natural compound with tumor-suppressive properties in non-small cell lung cancer (NSCLC).
  • The mechanisms by which Mor sensitizes cells to cisplatin (DDP) and its direct molecular targets remain underexplored.

Purpose of the Study:

  • To investigate the DDP-sensitizing effects of Mor in NSCLC.
  • To elucidate the underlying molecular mechanisms of Mor's action, including its direct targets and pathways involved.

Main Methods:

  • Cell viability and drug synergy assays were performed in NSCLC and DDP-resistant cells.
  • Ferroptosis was assessed by measuring lipid reactive oxygen species (ROS), iron accumulation, and ferroptosis marker expression.
  • GDF15 was identified as a Mor target via transcriptome sequencing and validated using molecular docking, proteasome inhibition, and GDF15 overexpression/knockdown models.

Main Results:

  • Morusin (Mor) significantly enhanced DDP sensitivity in both NSCLC and cisplatin-resistant A549 cells by inducing ferroptosis.
  • Mor directly binds to GDF15, promoting its ubiquitin-mediated degradation, which was crucial for Mor's observed effects.
  • GDF15 knockdown increased DDP sensitivity in resistant cells, while GDF15 overexpression reversed Mor-induced cytotoxicity and DDP sensitization.

Conclusions:

  • Morusin reverses DDP resistance in NSCLC by inducing GDF15 degradation and promoting ferroptosis.
  • Mor-based combination therapy presents a promising strategy for treating NSCLC, particularly in overcoming DDP resistance.
Keywords:
GDF15NSCLCcisplatinferroptosismorusin

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