Tmprss6 modulates radiation-induced liver injury through the hepcidin axis and PI3K/AKT pathway.

Background: Radiation-induced liver injury (RILI) poses a significant challenge in abdomino-pelvic tumor radiotherapy, adversely impacting normal liver tissues. This study explores the role of Tmprss6, a gene encoding Matriptase2, in acute RILI development and its impact on hepatocyte apoptosis.

Methods: A RILI model was established using 30 Gy total liver irradiation in C57BL/6J mice. Expression of Tmprss6 and hepcidin post radiation was detected by immunohistochemistry staining, Western blot and quantitative real-time PCR. Tmprss6 knockout mice were established to demonstrate the contribution of Tmprss6 to RILI. The molecular response within the liver after Tmprss6 knockdown was investigated using Transcriptomics sequencing.

Results: Disruptions in the Matriptase2-hepcidin axis emerge post-total liver radiation, marked by decreased Matriptase2 levels and heightened hepcidin levels. Tmprss6 knockout exacerbates RILI, evident in reduced mouse survival, increased liver damage, and elevated serum levels of aminotransferases. Additionally, Tmprss6 deletion increases inflammatory cytokines and malondialdehyde level while diminishing liver antioxidant capacity. Gene expression profiling reveals shifts in inflammation, apoptosis, and p53 signaling pathways upon Tmprss6 deletion. In vitro experiments, utilizing the AKT inhibitor AZD5363, demonstrate its effectiveness in reversing impediments caused by Tmprss6 silencing post-radiation. AZD5363 effectively restores suppressed cell proliferation, mitigates heightened cell apoptosis, and counters the elevated p53 expression induced by Tmprss6 depletion. This underscores the partial mediation of Tmprss6's protective role through the PI3K-AKT signaling.

Conclusions: This study unveils intricate mechanistic pathways activated by Tmprss6 silencing, amplifying p53 expression, facilitating hepatocyte apoptosis, and accelerating RILI progression, which providing nuanced insights into the multifaceted involvement of Tmprss6 in RILI.