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Enocyanin Synergistically Enhances Sorafenib Sensitivity in Hepatocellular Carcinoma via Ferroptosis Induction

Mengting Tian1, Jing Ma2, Tingting Wei3

  • 1School of Pharmacy, Ningxia Medical University, Yinchuan 750004, China.

Current Issues in Molecular Biology
|April 27, 2026
PubMed

Insights

Enocyanin (Eno), a grape extract, induces ferroptosis to combat hepatocellular carcinoma (HCC). Combining Eno with sorafenib synergistically enhances anti-tumor effects and overcomes resistance, showing promise for HCC treatment.

Area of Science:

  • Oncology
  • Pharmacology
  • Biochemistry

Background:

  • Hepatocellular carcinoma (HCC) presents a significant global health challenge due to limited effective treatments.
  • Sorafenib, a first-line HCC therapy, often encounters acquired resistance, necessitating novel therapeutic strategies.
  • Enocyanin (Eno), a natural anthocyanin extract from grapes, is explored for its anti-cancer potential.

Purpose of the Study:

  • To investigate the anti-HCC effects of Enocyanin (Eno) alone and in combination with sorafenib.
  • To elucidate the underlying mechanism of Eno's anti-cancer activity, focusing on ferroptosis induction.
  • To evaluate the synergistic potential of Eno and sorafenib as a combined therapeutic approach for HCC.

Main Methods:

  • In vitro studies using HepG2 cells to assess proliferation, invasion, and migration.
  • Analysis of ferroptosis markers: intracellular Fe2+, lipid peroxidation (LPO), ACSL4, GSH, and GPX4 levels.
  • Investigation of the p62/Keap1/Nrf2/HO-1 signaling pathway.
  • In vivo studies using a C57BL/6 mouse subcutaneous HCC transplantation model.

Main Results:

  • Enocyanin (100 μg/mL) significantly inhibited HepG2 cell proliferation, invasion, and migration.
  • Eno induced ferroptosis by increasing Fe2+, LPO, and ACSL4, while decreasing GSH and GPX4.
  • Eno suppressed the p62/Keap1/Nrf2/HO-1 pathway, mediating ferroptosis.
  • The combination of Eno (100 μg/mL) and sorafenib (2 μM) exhibited synergistic anti-tumor effects (Q=1.47).
  • Combined therapy enhanced tumor growth inhibition (70%) in mice compared to monotherapies (Eno: 33%, Sorafenib: 55%).

Conclusions:

  • Enocyanin acts as a novel inducer of ferroptosis, demonstrating significant potential for hepatocellular carcinoma treatment.
  • The combination of Enocyanin and sorafenib offers a promising synergistic strategy to enhance HCC therapy and overcome sorafenib resistance.
  • Targeting the p62/Keap1/Nrf2/HO-1 pathway with Enocyanin presents a viable therapeutic avenue for HCC.
Keywords:
EnocyaninHepG2ferroptosishepatocellular carcinomap62/Keap1/Nrf2/HO-1sorafenib

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