ORIGINAL RESEARCH article
Front. Physiol.
Sec. Renal Physiology and Pathophysiology
Volume 16 - 2025 | doi: 10.3389/fphys.2025.1672201
This article is part of the Research TopicCardiovascular–Kidney–Metabolic Syndrome: Interorgan Crosstalk, Pathophysiology, and TherapeuticsView all 3 articles
Acute Kidney Injury Following Fatty Liver Ischemia-Reperfusion Injury: Indirect Protection by Hepatic Ferroptosis Inhibition
Provisionally accepted
Wenjun Zhang1*
Zachary Rokop2Shan Li2
Christina Ferreria3
Shunhua Guo2
WEINIAN SHOU2Pierre Dagher2
Chandan K Sen2Sylvester Black4Chandrashekhar Kubal2- 1School of Medicine, Indiana University Bloomington, Indianapolis, United States
- 2Indiana University School of Medicine, Indianapolis, United States
- 3Purdue University, West Lafayette, United States
- 4The Ohio State University College of Medicine, Columbus, United States
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Background: The association between hepatic ischemia-reperfusion injury (hIRI) in steatotic livers and subsequent acute kidney injury (AKI) is well established. Ferroptosis plays a critical role in fatty liver IRI. However, whether ferroptosis also contributes to secondary AKI following hIRI remains unclear. Methods: hIRI was induced in mice fed either a high-fat, high-sucrose diet (HFD) or a normal diet (ND) to mimic the AKI commonly observed clinically after fatty liver transplantation. Kidney injury mechanisms were evaluated using histopathology, RNA sequencing, electron microscopy, and biochemical assays. Ferroptosis in the kidney was assessed by quantifying ACSL4, 4-hydroxynonenal (4-HNE), and AA-PE in homogenates and tissue sections. In parallel experiments, the lipid peroxidation inhibitor Liproxstatin-1 (Lip-1) was administered prior to hIRI to inhibit ferroptosis. Results: AKI severity was markedly increased in HFD-fed mice compared to ND controls following hIRI. Histological, transcriptomic, and cytokine analyses revealed that apoptosis and inflammation were the primary mechanisms of kidney injury after HFD+hIRI. Kidney levels of ACSL4 and 4-HNE were not significantly elevated in either group after hIRI. Lip-1 treatment significantly reduced both liver injury and AKI in HFD-fed mice but showed no protective effect in ND-fed animals. Conclusions: Apoptosis and inflammation are the prominent kidney injury mechanisms involved in AKI following fatty liver IRI. Although ferroptosis may not be directly involved in the renal injury, anti-ferroptotic intervention mitigates AKI, supporting the concept that ferroptosis-mediated liver injury may serve as the primary upstream trigger in this context.
Keywords: Acute Kidney Injury, Fatty Liver, ischemia-reperfusion injury, ferroptosis, Apoptosis, Inflammation
Received: 24 Jul 2025; Accepted: 11 Sep 2025.
Copyright: © 2025 Zhang, Rokop, Li, Ferreria, Guo, SHOU, Dagher, Sen, Black and Kubal. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Wenjun Zhang, wenzhang@iu.edu
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