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Targeting GPX4-mediated Ferroptosis Alleviates Liver Steatosis in a Rat Model of Total Parenteral Nutrition
Siyang Cheng1, Ying Wang2, Yuling Zhao1
1Division of Pediatric Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China; Shanghai Institute for Pediatric Research, Shanghai, China.
Background:
Parenteral nutrition-associated liver disease (PNALD) is a common hepatobiliary complication resulting from long-term parenteral nutrition (PN) that is associated with significant morbidity and mortality. Ferroptosis plays a significant role in the pathogenesis of various liver diseases. This study aims to explore the role of ferroptosis in PNALD and to uncover its underlying mechanisms.
Methods:
Ferroptosis was evaluated in pediatric patients with PNALD and in rats administered with total parenteral nutrition (TPN) as an animal model of PNALD. In TPN-fed rats, we applied liproxstatin-1 (Lip-1) to inhibit ferroptosis for 7 days and assessed its impact on liver steatosis. We performed RNA-seq analysis to profile the alterations in miRNAs in livers from TPN-fed rats. The ferroptosis-promoting effects of miR-431 were evaluated in HepG2 cells and the direct targeting effects on glutathione peroxidase 4 (GPX4) were evaluated in HEK293T cells.
Results:
RNA-seq analysis and experimental validation suggested that ferroptosis was increased in the livers of pediatric patients and rats with PNALD. Inhibiting ferroptosis with Lip-1 attenuated liver steatosis by regulating PPARα expression. RNA-seq analysis uncovered miR-431 as the most upregulated miRNA in the livers of TPN-fed rats, showing a negative correlation with hepatic GPX4 expression. In vitro studies demonstrated that miR-431 promoted ferroptosis by directly binding to the 3'UTR of GPX4 mRNA, resulting in the suppression of its expression.
Conclusions:
Our study demonstrates that TPN induces the upregulation of miR-431 in rats, leading to activation of ferroptosis through downregulation of GPX4. Inhibition of ferroptosis attenuates TPN-induced liver steatosis by regulating PPARα expression.
