NUPR1 inhibitor ZZW-115 induces ferroptosis in a mitochondria-dependent manner

Area of Science:

• Cell Death Research
• Biochemistry
• Oncology

Background:

• Ferroptosis is an iron-dependent cell death pathway marked by lipid hydroperoxide accumulation.
• Pancreatic ductal adenocarcinoma (PDAC) and hepatocellular carcinoma (HCC) are significant health concerns.
• Understanding novel cell death inducers and regulators is crucial for cancer therapy.

Purpose of the Study:

• To investigate the mechanism of cell death induced by the NUPR1 inhibitor ZZW-115.
• To explore the role of reactive oxygen species (ROS), lipid peroxidation, and mitochondrial function in ZZW-115-induced cell death.
• To determine if TFAM (mitochondrial transcription factor A) can counteract this cell death pathway.

Main Methods:

• Treatment of PDAC and HCC cell lines with ZZW-115.
• Assessment of cell death using ferroptosis inhibitors (Fer-1) and ROS scavengers.
• Analysis of lipid peroxidation, antioxidant enzyme activity (GSH, GPX), and mitochondrial morphology/function.
• In vivo validation using PDAC and HCC xenografts in nude mice.
• Investigation of TFAM expression and its rescue effects.

Main Results:

• ZZW-115 induced ROS accumulation and ferroptotic cell death, preventable by Fer-1 and ROS scavengers.
• Inhibition of antioxidant factors enhanced ZZW-115's ferroptotic activity.
• ZZW-115 caused mitochondrial morphological changes, network disorganization, and metabolic dysfunction.
• TFAM expression was downregulated by ZZW-115, and its forced expression rescued ZZW-115-induced toxicity.
• Results were validated in vivo in PDAC and HCC xenograft models.

Conclusions:

• ZZW-115 is a potent inducer of ferroptosis, involving ROS, lipid peroxidation, and mitochondrial dysfunction.
• TFAM acts as a crucial antagonist of NUPR1 inhibitor-mediated ferroptosis.
• TFAM represents a potential therapeutic target for managing ferroptosis in cancers like PDAC and HCC.