# Acute Stress Attenuates Hepatic Ischemia–Reperfusion Injury via Hypothalamic CRH Neuron‐Induced HPA Axis Activation

## TL;DR

Acute stress protects the liver from injury during surgery by activating a brain pathway that reduces inflammation.

## Contribution

Identifies a novel neuroendocrine mechanism where hypothalamic CRH neurons mediate stress-induced protection against liver injury.

## Key findings

- Acute restraint stress reduces liver injury and inflammation in mice via HPA axis activation.
- PVNCRH neurons are critical for stress-induced protection against hepatic ischemia–reperfusion injury.
- Chemogenetic manipulation confirms the role of PVNCRH neurons in mediating this protective effect.

## Abstract

Hepatic ischemia–reperfusion injury (HIRI) is a pathologic process commonly encountered during liver surgery, which seriously threatens patient prognosis. Currently, effective interventions or preventive measures are still lacking. Notably, patients with liver disease commonly experience brief acute stress prior to surgery; however, the impact of acute stress on HIRI remains unclear.

A 30‐min restraint stress was used to simulate acute restraint stress (ARS). Hematoxylin–eosin staining and ELISA were employed to assess HIRI. Immunofluorescence staining and electrophysiology were applied to evaluate neuronal activation. Chemogenetic manipulation was utilized to verify the role of corticotropin‐releasing hormone (CRH) neurons in the hypothalamic paraventricular nucleus (PVN) in ARS‐mediated attenuation of HIRI.

The results showed that ARS significantly ameliorated liver injury, reduced the liver enzyme levels (ALT and AST), and down‐regulated the inflammatory factors expression in HIRI mice. Furthermore, we found that ARS alleviated HIRI by activating the hypothalamic–pituitary–adrenal (HPA) axis to release corticosterone, rather than through the sympathetic nervous system. PVNCRH represented a critical subpopulation responding to ARS. Chemogenetic activation of PVNCRH neurons mimicked the protective effect of ARS against HIRI, whereas chemogenetic inhibition of these neurons abolished this protection.

Our findings demonstrate that PVNCRH neurons mediate the protective effect of ARS against HIRI by activating the HPA axis to release corticosterone. This work may provide key insights for developing perioperative strategies to prevent HIRI.

This study demonstrates the protective effect of acute restraint stress (ARS) against hepatic ischemia–reperfusion injury (HIRI) in mice and investigates its specific neuroendocrine mechanisms. During ARS, excitability of PVNCRH neurons significantly increases, which drives HPA axis to release corticosterone, thereby reducing hepatic inflammation and ultimately alleviating HIRI.