Sophoridine derivative 6j inhibits liver cancer cell proliferation via ATF3 mediated ferroptosis

Area of Science:

• Oncology
• Biochemistry
• Pharmacology

Background:

• Liver cancer is a leading cause of cancer death, with limited first-line targeted therapies like sorafenib and lenvatinib.
• Targeting ferroptosis, an iron-dependent programmed cell death, presents a promising strategy for liver cancer treatment.
• Activating transcription factor 3 (ATF3) is identified as a key inducer of ferroptosis, offering a potential therapeutic target.

Purpose of the Study:

• To investigate the anti-liver cancer effects of a novel sophoridine derivative, compound 6j.
• To elucidate the mechanism by which compound 6j induces liver cancer cell death, focusing on ferroptosis.
• To explore the role of ATF3 in mediating the anti-cancer effects of compound 6j.

Main Methods:

• In vitro and in vivo studies were conducted using liver cancer cell lines and animal models.
• Ferroptosis was assessed by measuring intracellular iron (Fe2+), reactive oxygen species (ROS), and malondialdehyde (MDA) levels.
• The role of ATF3 was investigated using RNA interference (RNAi) to knock down ATF3 expression.
• Endoplasmic reticulum (ER) stress was analyzed as a potential mediator of ATF3 upregulation.

Main Results:

• Compound 6j demonstrated significant anti-liver cancer activity in vitro and in vivo.
• 6j induced ferroptosis in liver cancer cells by increasing Fe2+, ROS, and MDA accumulation.
• Ferrostatin-1, a ferroptosis inhibitor, reversed the effects of 6j, confirming ferroptosis induction.
• Compound 6j upregulated ATF3 expression through ER stress.
• Knockdown of ATF3 attenuated 6j-induced ferroptosis and inhibited cell proliferation.

Conclusions:

• Compound 6j is a potent inducer of ferroptosis in liver cancer cells.
• The anti-cancer effects of compound 6j are mediated, at least in part, by the upregulation of ATF3 via ER stress.
• This study provides a basis for designing novel ferroptosis inducers and developing new anti-liver cancer therapeutics.