Jujuboside B Induces Ferroptosis and Overcomes Radioresistance Through the PPARγ-ATF3-Gpx4 Signaling Pathway in...

Area of Science:

• Pharmacology
• Oncology
• Molecular Biology

Background:

• Jujuboside B (JJB), a saponin from Ziziphus jujuba, exhibits anticancer properties, but its mechanism in non-small cell lung cancer (NSCLC) is not fully understood.
• Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resistance is a challenge in NSCLC treatment.
• PPARγ modulation by JJB suggests potential therapeutic applications.

Purpose of the Study:

• To investigate the synergistic anti-cancer effects of combining JJB with TRAIL in NSCLC cells.
• To elucidate the underlying mechanisms, including endoplasmic reticulum (ER) stress and ferroptosis.
• To evaluate JJB's potential in overcoming radioresistance in NSCLC models.

Main Methods:

• Cell viability assays (ATPlite Luminescence, LDH) and caspase activity assays were used to assess cell death.
• Intracellular calcium assays and western blot analysis were employed to examine ER stress.
• Gene and protein expression levels related to ferroptosis, ER stress, and epithelial-mesenchymal transition (EMT) were analyzed.

Main Results:

• The combination of JJB and TRAIL significantly enhanced NSCLC cell death via apoptosis, involving CHOP binding to the DR4/5 promoter.
• JJB induced ferroptosis by activating ER stress, upregulating Nox4 and ATF3, increasing MDA and ROS, and downregulating SLC7A11, Gpx4, and GSH.
• N-acetylcysteine (NAC) reversed JJB-induced ferroptosis, confirming the role of ER stress.
• Combined JJB and radiation therapy overcame radioresistance in NSCLC models by inducing ferroptosis and modulating EMT.

Conclusions:

• JJB exhibits synergistic anti-cancer effects with TRAIL and radiation in NSCLC.
• JJB induces NSCLC cell death through apoptosis and ferroptosis, mediated by ER stress.
• JJB holds promise as a therapeutic agent for overcoming TRAIL resistance and radioresistance in NSCLC.