Psychological distress is associated with increased liver disease mortality. This association highlighted the close relationship between psychological and physical health. Thus, further work to elucidated the underlying mechanism should be carried out. In this experiment, a model of anxious rats was established by compound stress. The HPA axis situation and inflammatory factor changes in the brain of the rats were observed, which in turn were evaluated for behavioral tests and liver function, respectively. The liver metabolic profiles of the rats were characterized by liquid chromatography-mass spectrometry (LC-MS). Differential metabolites were screened by p < 0.05 and VIP > 1. Pathway enrichment analysis was performed on metabolomics data by Ingenuity Pathway Analysis (IPA). Immunofluorescence (IF), immunohistochemistry (IHC) and western blotting, were employed to detect the expression of the screened target epidermal growth factor receptor (EGFR), and verify its potential pathway of mechanism. The results show that we found liver function impairment in anxiety-like rats. Further, 61 differential metabolites in control and anxiety groups were screened by using metabolomics (p < 0.05, VIP > 1). IPA analysis revealed the key target EGFR which was also identified from the HPA axis. We further found that anxiety-like rats may cause liver injury through EFGR/PI3K/AKT/NF-κB pathway, and then lead to the production of inflammatory factors in the liver. This study demonstrated that the activation of HPA axis in anxiety-like rats led to phosphorylation of EGFR, which finally contributed to liver injury through the EGFR/PI3K/AKT/NF-κB pathway. This finding provided novel evidence for the deleterious effects of psychological problems on physical health.

Hepatic fibrosis (HF) could be developed into liver cirrhosis or even hepatocellular carcinoma. Stress has an important role in the occurrence and development of various considerable diseases. However, the effect of a certain degree stress on HF is still controversial. In our study, stress was simulated with regular chronic restraint stress (CRS) and HF model was induced with CCl4 in mice. We found that CRS was able to attenuate CCl4-induced liver injury and fibrosis in mice. Surprisingly, behavioral analysis showed that the mice in the HF group exhibited depression-like behavior. Further, the metabolomic analysis revealed that 119 metabolites and 20 metabolic pathways were altered in mice liver, especially the betaine metabolism pathway. Combined with the results of ingenuity Pathway Analysis (IPA) analysis, the key proteins INSR, PI3K, AKT, and p-AMPK were identified and verified, and the results showed that CRS could upregulate the protein levels and mRNA expression of INSR, PI3K, AKT, and p-AMPK in liver tissues of HF mice. It suggested that CRS alleviated CCl4-induced liver fibrosis in mice through upregulation of the INSR/PI3K/AKT/AMPK pathway. Proper stress might be a potential therapeutic strategy for the treatment of chronic liver disease, which provided new insights into the treatment of HF.

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