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Updated: Jan 11, 2026

Drug-Induced Senescence in Liver Cells Promotes M2 Macrophage Polarization: Implications for Tyrosine Kinase Inhibitor-Associated Hepatotoxicity
09:32

Drug-Induced Senescence in Liver Cells Promotes M2 Macrophage Polarization: Implications for Tyrosine Kinase Inhibitor-Associated Hepatotoxicity

Published on: October 17, 2025

412

Corynoline enhances sorafenib sensitivity in hepatocellular carcinoma via NOS3-mediated ROS production

Qiaoli Yi1,2, Xi Chen1, Shangjun Zhou1

  • 1Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.

Chinese Medicine
|November 13, 2025
PubMed
Abstract

Insights

Cory alkaloids synergize with sorafenib to treat advanced liver cancer. This combination enhances treatment efficacy by increasing reactive oxygen species (ROS) and IL-18 secretion via NOS3, overcoming sorafenib resistance.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Sorafenib (Sora) efficacy in advanced hepatocellular carcinoma (HCC) is limited by moderate effectiveness and acquired resistance.
  • Combination therapy presents a promising strategy to enhance therapeutic outcomes in HCC treatment.

Purpose of the Study:

  • To screen alkaloids for synergistic anticancer effects with low-dose sorafenib in HCC.
  • To elucidate the underlying molecular mechanisms of this synergistic interaction.

Main Methods:

  • Cell viability was assessed using CCK-8 assays.
  • Molecular docking, CETSA, and DARTS were used to identify and validate drug targets.
  • Reactive oxygen species (ROS) levels and IL-18 secretion were quantified.
  • Nude mouse xenograft models were utilized for in vivo validation.

Main Results:

  • Cory, an alkaloid, demonstrated significant synergistic anticancer effects when combined with sorafenib.
  • Nitric oxide synthase 3 (NOS3) was identified as a direct binding target of Cory.
  • The combination therapy enhanced HCC cell sensitivity to sorafenib through NOS3-mediated ROS production and IL-18 secretion.
  • NOS3 knockdown reversed the synergistic effect, while NAC administration mitigated ROS and IL-18 increases.

Conclusions:

  • Cory acts synergistically with sorafenib to inhibit HCC growth.
  • The mechanism involves NOS3-mediated ROS production and IL-18 secretion, sensitizing HCC cells to sorafenib.
  • Cory shows potential as a sorafenib sensitizer for advanced HCC treatment.
Keywords:
CorynolineHepatocellular carcinomaNOS3ROSSorafenib

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