Aim of the study

This study aimed to investigate the potential role of the Th17/IL-17 pathway in the pathogenesis and progression of acute-on-chronic liver failure (ACLF), with a particular focus on whether interleukin (IL)-17 may promote ferroptosis through the TP53/Nrf2 signaling pathway.

Material and methods

Transcriptomic sequencing was performed to identify signaling pathways and hub genes associated with ACLF. The Th17 signaling pathway and TP53 were selected for further investigation. In vitro, L-02 cells were treated with IL-17 to establish an in vitro hepatocyte injury model. Reactive oxygen species (ROS) levels, intracellular iron content, cellular structural changes, and the expression of ferroptosis-related genes and proteins, including SLC7A11, GPX4, ACSL4, TRIM25, p53, and Nrf2, were analyzed and compared with untreated controls.

Results

Transcriptomic analysis indicated that the Th17 signaling pathway was closely associated with ACLF, and TP53 was identified as a potential hub gene implicated in liver failure. In IL-17-treated L-02 cells, ROS levels and intracellular iron content were significantly elevated compared with untreated controls. The expression levels of SLC7A11 and GPX4 were significantly lower, whereas ACSL4 and TRIM25 expression levels were significantly higher. In addition, IL-17 stimulation led to significant upregulation of p53 and downregulation of Nrf2, accompanied by ferroptosis-related oxidative stress and cellular structural alterations.

Conclusions

These findings suggest that Th17/IL-17 may contribute to the pathogenesis and progression of ACLF by inducing ferroptosis in hepatocytes. The observed upregulation of p53 and downregulation of Nrf2 indicate that IL-17 may promote ferroptosis through the TP53/Nrf2 signaling pathway. This mechanism may provide a rationale for further investigation of potential therapeutic targets in ACLF.