Th17/IL-17F Activates the TP53/Nrf2 Signaling Pathway-Mediated Ferroptosis and Plays an Important Role in Acute-on-Chronic Liver Failure

Liver failure is a critical condition caused by various factors, leading to extensive hepatocyte necrosis, severe hepatic dysfunction, and ultimately systemic multi-organ failure. Acute-on-chronic liver failure (ACLF) is the most prevalent form of liver failure in Asia. The pathogenesis of ACLF is complex. Transcriptomic sequencing revealed that the Th17 signaling pathway is closely associated with ACLF, and TP53 is a core gene implicated in liver failure. In addition, ferroptosis also plays an important role in ACLF. In vitro, we found that reactive oxygen species (ROS) levels and iron content were significantly increased in IL-17-treated L-02 cells compared with untreated controls. Compared with the control group, the expression levels of SLC7A11 and GPX4 were significantly decreased, while ACSL4 and TRIM25 were significantly increased in the IL-17 treatment group. We also observed a significant upregulation of P53 and a downregulation of Nrf2. This study suggests that TP53 may play a key role in ACLF by mediating ferroptosis. Experimental results confirmed that IL-17 stimulation induced ferroptosis-related oxidative stress, structural alterations in cells, and differential expression of ferroptosis-related genes. Most importantly, changes in P53 and Nrf2 expression following IL-17 treatment suggest that Th17/IL-17 may promote ferroptosis through the TP53/Nrf2 signaling pathway and thereby contribute to the pathogenesis and progression of liver failure.