Iron deficiency aggravates hepatic inflammation in suckling piglets via endoplasmic reticulum stress-driven NF-κB pathway activation

TL;DR

Iron deficiency in piglets worsens liver inflammation by activating a stress pathway that triggers inflammation.

Contribution

This study reveals a new mechanism linking iron deficiency to liver inflammation via endoplasmic reticulum stress and NF-κB activation.

Findings

Iron deficiency causes oxidative stress and disrupts antioxidant pathways in piglet livers.

Endoplasmic reticulum stress activates the TLR4/NF-κB pathway, increasing pro-inflammatory cytokines.

Pharmacological inhibition of endoplasmic reticulum stress reduces inflammation in iron-deficient livers.

Abstract

Iron deficiency (ID) poses a significant health burden to both human infants and suckling piglets. In piglets, ID leads to substantial economic losses for the industry by compromising growth performance, health, and survival. However, current research has predominantly concentrated on hematological abnormalities, whereas the mechanisms underlying ID-associated hepatic inflammatory injury remain inadequately elucidated. Our study employed the iron-deficient suckling piglet model to address this knowledge gap and to establish a molecular theoretical foundation.

To investigate the underlying mechanisms, this study conducted in vivo and in vitro models. In piglets, ID triggered hepatic oxidative stress by inducing a redox imbalance and suppressing the core Nrf2/HO-1 antioxidant signaling pathway. Histopathological examination revealed structural abnormalities in ID piglet livers, including disorganized hepatic cords, cytoplasmic vacuolation, hydropic degeneration, and mononuclear inflammatory cell infiltration. Transmission electron microscopy further showed shrunk nuclear envelopes, reduced numbers of rough endoplasmic reticulum (RER), and dilated RER cisternae in hepatocytes of ID piglets. Mechanistically, ID activated endoplasmic reticulum stress (ERS) and the PERK/IRE1α branches of the unfolded protein response (UPR). RNA-seq transcriptomic analysis demonstrated significant dysregulation of immune-related pathways, accompanied by elevated pro-inflammatory cytokines (e.g., IL1B, TNF) and decreased anti-inflammatory cytokines (e.g., IL4, IL10). Central to this inflammatory response was the activation of the TLR4/NF-κB pathway, evidenced by upregulation of MyD88 and increased phosphorylation of IκBα and NF-κB p65. In vitro, deferoxamine (DFO)-induced ID in AML12 hepatocytes consistently recapitulated the key features of this phenotype, including the activation of ERS/ UPR and the TLR4/NF-κB signaling pathway. Pharmacological inhibition of ERS by 4-phenylbutyric acid (4-PBA) attenuated DFO-induced NF-κB activation and ameliorated the imbalance between pro- and anti-inflammatory cytokines.

ID exacerbated hepatic inflammation through ERS-mediated activation of the NF-κB pathway, providing novel mechanistic insights into liver injury associated with ID.

The online version contains supplementary material available at 10.1186/s40104-026-01356-4.

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