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

ABSTRACT Background 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. Methods 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. Results 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. PVN CRH represented a critical subpopulation responding to ARS. Chemogenetic activation of PVN CRH neurons mimicked the protective effect of ARS against HIRI, whereas chemogenetic inhibition of these neurons abolished this protection. Conclusion Our findings demonstrate that PVN CRH 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.