# Surgery and Acute Stress Decrease NRF2 mRNA Expression and Promote Iron Metabolism Alteration, Oxidative Stress, and Inflammatory Gene Expression in the Liver of Prehypertensive Rats

## TL;DR

Surgery and stress in prehypertensive rats reduce liver antioxidant defenses and increase iron changes, leading to oxidative stress and inflammation, which may cause liver damage.

## Contribution

This study reveals that non-hepatic surgery and acute stress induce a pro-ferroptotic state in the liver, contributing to post-surgical injury.

## Key findings

- Surgery and stress reduced NRF2 and GPX4 mRNA in the liver, indicating impaired antioxidant defenses.
- Increased hepatic iron-related gene expression and oxidative markers suggest a pro-ferroptotic state.
- Combined surgery and stress caused iron accumulation in liver tissue, potentially worsening liver damage.

## Abstract

This study investigated how non-hepatic surgery and subsequent acute stress affect iron distribution, redox state, antioxidant defence, and inflammation-related gene expressions and iron metabolism in the liver of borderline hypertensive rats. We used air-jet stress as a model of acute psychological stress (3 sessions of 5 sec. air-jet) applied approximately 22 hours post-surgery (carotid artery and jugular vein cannulation). Both the surgery (Su) and post-surgical stress (Su+Str) increased corticosterone and reduced iron concentrations in plasma, while increasing remanent magnetisation (Mr) and coercivity (Hc) in whole blood. In the liver, Su and Su+Str reduced mRNA expressions of genes encoding NFR2 and GPX4 proteins (Nfe2l2 and Gpx4, respectively), and induced a significant increase in hepatic conjugated dienes, proinflammatory factors (Il1b) and iron-regulating genes mRNA (Hmox1, Fpn1, Fth1, Hamp, Tfr1), despite elevated Hmox1 and Sod1 mRNA expressions. In addition, hepatic Mr and Hc after Su and Su+Str were elevated, suggesting a qualitative change of iron-containing substances in circulation and liver tissue. In addition, in the Su+Str group, the elevated saturation magnetisation (Ms) is indicative of elevated total iron content. These findings suggest that a mild non-hepatic surgery may reduce hepatic mRNA expression of NRF2 and GPX4, which was associated with oxidative tissue damage accompanied by qualitative alterations in cellular iron, indicating a pro-ferroptotic state that, together with enhanced inflammation, may contribute to post-surgical liver injury. Additionally, the combination of surgery and acute post-surgical stress led to tissue iron accumulation, which may contribute to liver damage.