Irisin prevents liver injury during exhausting physical activity by suppressing ferroptosis via Nrf2/GPX4 signaling

Background: Irisin, a recently identified protein that is released during exercise and promotes the transformation of white adipocytes into brown adipocytes. The expression of irisin in the liver suggests its possible involvement in liver function and performance, however it has not been comprehensively investigated.

Methods: The investigation included creating exhaustive exercise (EE) models using 8-week-old C57BL/6 mice. Following exhaustion exercise, irisin was administered intraperitoneally on a daily basis. The liver damage was assessed by HE staining and by measuring the levels of ALT (alanine aminotransferase) and AST (aspartate aminotransferase). The impact of irisin on liver inflammation levels during EE was assessed using ELISA and qRT-PCR. The impact of irisin on Ferroptosis was assessed by measuring the levels of GSH (glutathione), GPX4 (Glutathione Peroxidase 4), MDA (malondialdehyde), and Fe²⁺. The concentrations of MDA, ASCL4 (achaete-scute family bHLH transcription factor 4), ALOX12 (arachidonate 12-lipoxygenase), GPX4, SLC7A11 (solute carrier family 7 member 11), and Nrf2 (nuclear factor erythroid 2 - related factor 2) were assessed by the administration of the Nrf2 inhibitor ML385 via intraperitoneal injection. This study was carried out to investigate the underlying mechanism of irisin in relation to liver damage during EE.

Results: This research discovered that EE resulted in liver damage, disruption of liver cell organization, increased levels of ALT and AST Enzymes (all P < 0.001), and raised levels of inflammatory cytokines and chemokines (all P < 0.001). Simultaneously, EE triggered hepatic Ferroptosis, as evidenced by elevated levels of ROS (Reactive Oxygen Species) (P < 0001), Fe²⁺ (P < 0.001), and MDA (P < 0.001), decreased levels of GSH (P < 0.001), and altered expression of proteins associated with Ferroptosis (GPX4, ACSL4, and SLC7A11). Conversely, irisin mitigated the disorderly arrangement of hepatic cells, sinus dilation in the liver, and hepatic cell Ferroptosis induced by exercise. Nevertheless, the Nrf2 inhibitor ML385 effectively abolished irisin-mediated Ferroptosis.

Conclusion: These findings indicate that irisin has the ability to safeguard the liver from damage caused by intense exercise by suppressing Ferroptosis triggered by the Nrf2/GPX4 signaling pathway and reducing the inflammatory response after oxidative stress. These results provide novel perspectives on the correlation between irisin and liver disease.

Trial registration: Not applicable.

Exhaustive exercise; Ferroptosis; Irisin; Liver injury; Nrf2/GPX4 signaling.