Inhibition of STAT3-NF-κB pathway facilitates SSPH I-induced ferroptosis in HepG2 cells

Area of Science:

• Oncology
• Cell Biology
• Biochemistry

Background:

• Hepatocellular carcinoma (HCC) is a lethal cancer with limited treatment options.
• Ferroptosis, a form of regulated cell death, shows promise in HCC treatment.
• The roles of STAT3 and Nf-κB in ferroptosis regulation within HCC remain incompletely understood.

Purpose of the Study:

• To investigate the interplay between STAT3 and Nf-κB in regulating ferroptosis in HCC.
• To determine the effect of inhibiting STAT3 and Nf-κB on ferroptosis induction by SSPH I.
• To elucidate the molecular mechanisms underlying STAT3 and Nf-κB mediated ferroptosis in HCC cells.

Main Methods:

• Utilized HepG2 cells, a human HCC cell line.
• Employed specific inhibitors: Stattic for STAT3 and Bay11-7082 for Nf-κB.
• Administered ferroptosis inducer SSPH I and analyzed its effects on cell viability, iron metabolism, oxidative stress markers, and protein expression.

Main Results:

• Inhibition of STAT3 and Nf-κB significantly enhanced SSPH I-induced ferroptosis and cytotoxicity.
• SSPH I treatment altered iron metabolism proteins and GPX4, triggering STAT3-dependent Nf-κB activation.
• Combined inhibition of STAT3 and Nf-κB increased reactive oxygen species (ROS), malondialdehyde (MDA), and Fe²⁺ levels, while depleting glutathione (GSH), intensifying lipid peroxidation and iron overload.

Conclusions:

• Targeting STAT3 and Nf-κB pathways can potentiate ferroptosis in HCC.
• Understanding the STAT3-Nf-κB axis provides novel insights into ferroptosis mechanisms in liver cancer.
• This study highlights the therapeutic potential of combining ferroptosis inducers with STAT3/Nf-κB inhibitors for HCC treatment.