Peroxiredoxin II as a metabolic gatekeeper against aflatoxin B1-induced hepatic steatosis: restoration of PPARα/γ balance via mitochondrial ROS scavenging

Abstract

Aflatoxin B1 (AFB1), a pervasive food contaminant affecting approximately 25% of global staple crops, represents an underrecognized environmental risk factor for nonalcoholic fatty liver disease (NAFLD). This study investigates the protective role of peroxiredoxin II (Prx II), a mitochondrial antioxidant enzyme, against AFB1-induced hepatic steatosis and elucidates the underlying molecular mechanisms. Bioinformatic analysis of the publicly available AFB1-exposed liver transcriptome dataset (GSE26838) combined with gain- and loss-of-function studies in AML12 hepatocytes revealed that AFB1 induces lipid accumulation, mitochondrial reactive oxygen species (ROS) overproduction, and membrane potential depolarization, while simultaneously suppressing PPARα expression and upregulating PPARγ-a metabolic shift favoring lipid storage. Prx II knockdown exacerbated these pathological changes, whereas overexpression attenuated lipid accumulation (~ 60%) and mitochondrial ROS production (~ 58%), restoring PPARα activity and attenuating ROS-associated p38 MAPK activation and PPARγ upregulation. Pharmacological ROS scavenging with N-acetylcysteine (NAC) recapitulated the protective effects of Prx II overexpression, supporting ROS as an upstream contributor to AFB1-induced steatosis. These findings define a Prx II-ROS-PPARα/γ regulatory axis that mitigates AFB1-induced hepatic steatosis by scavenging mitochondrial ROS, preserving PPARα-dependent fatty acid oxidation, and dampening lipogenic signaling. Prx II emerges as a promising candidate biomarker and therapeutic target for aflatoxin-associated metabolic liver disease, with significant implications for food-safety risk assessment and intervention strategies in AFB1-endemic regions.