Ochratoxin A Induces Renal Cell Ferroptosis by Disrupting Iron Homeostasis and Increasing ROS.

Area of Science:

• Toxicology
• Cell Biology
• Food Safety

Background:

• Ochratoxin A (OTA) is a prevalent food contaminant with known nephrotoxic effects.
• The precise mechanisms underlying OTA-induced kidney damage, particularly oxidative stress, remain incompletely understood.
• Intracellular iron dysregulation is implicated in various cell death pathways, including ferroptosis.

Purpose of the Study:

• To investigate the role of intracellular iron in ochratoxin A-induced reactive oxygen species (ROS) accumulation.
• To determine if OTA induces iron-dependent ferroptotic cell death in human kidney cells.
• To elucidate the impact of OTA on cellular iron homeostasis.

Main Methods:

• Utilized human kidney cell lines exposed to ochratoxin A.
• Assessed cell viability, ferroptosis markers, and intracellular iron levels.
• Analyzed gene and protein expression of iron metabolism regulators (TFR1, FTH, FPN, Hepcidin).
• Employed iron chelators and ROS scavengers for mechanistic studies.

Main Results:

• Ochratoxin A treatment induced ferroptosis characteristics and reduced cell viability.
• OTA disrupted iron homeostasis by upregulating iron import (TFR1, FTH) and downregulating iron export (FPN), increasing Hepcidin.
• Intracellular iron accumulation, elevated ROS, and lipid peroxidation were observed following OTA exposure.
• Iron chelation significantly ameliorated OTA-induced toxicity, iron overload, and ROS production.
• ROS scavengers partially reversed OTA effects, indicating a secondary role compared to iron dysregulation.

Conclusions:

• Ochratoxin A induces ferroptotic cell death in renal cells primarily by disrupting iron homeostasis.
• OTA-induced intracellular iron accumulation is a key driver of oxidative stress and subsequent cell death.
• Targeting iron metabolism presents a potential therapeutic strategy against ochratoxin A nephrotoxicity.