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

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 <i>Tmprss6</i>, a gene encoding Matriptase2, in acute RILI development and its impact on hepatocyte apoptosis. A RILI model was established using 30 Gy total liver irradiation in C57BL/6J mice. Expression of <i>Tmprss6</i> and hepcidin post radiation was detected by immunohistochemistry staining, Western blot and quantitative real-time PCR. <i>Tmprss6</i> knockout mice were established to demonstrate the contribution of <i>Tmprss6</i> to RILI. The molecular response within the liver after <i>Tmprss6</i> knockdown was investigated using Transcriptomics sequencing. Disruptions in the Matriptase2-hepcidin axis emerge post-total liver radiation, marked by decreased Matriptase2 levels and heightened hepcidin levels. <i>Tmprss6</i> knockout exacerbates RILI, evident in reduced mouse survival, increased liver damage, and elevated serum levels of aminotransferases. Additionally, <i>Tmprss6</i> 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 <i>Tmprss6</i> deletion. In vitro experiments, utilizing the AKT inhibitor AZD5363, demonstrate its effectiveness in reversing impediments caused by <i>Tmprss6</i> silencing post-radiation. AZD5363 effectively restores suppressed cell proliferation, mitigates heightened cell apoptosis, and counters the elevated p53 expression induced by <i>Tmprss6</i> depletion. This underscores the partial mediation of <i>Tmprss6</i>’s protective role through the PI3K-AKT signaling. This study unveils intricate mechanistic pathways activated by <i>Tmprss6</i> silencing, amplifying p53 expression, facilitating hepatocyte apoptosis, and accelerating RILI progression, which providing nuanced insights into the multifaceted involvement of <i>Tmprss6</i> in RILI.