P110 The role of FOXO1 in post-transplant recurrence of hepatocellular carcinoma: a study on diagnostic and therapeutic targets

<h3>Background and Objective</h3> Hepatocellular carcinoma (HCC) is a highly prevalent and deadly malignancy in China. Although liver transplantation is the most effective treatment for HCC, tumor recurrence remains a significant challenge. Identifying precise diagnostic and therapeutic targets for post-transplant recurrence is crucial for improving HCC outcomes. This study aims to investigate the clinical association between FOXO1 and liver transplant outcomes in HCC patients and to explore the therapeutic potential of an esterase-responsive cationic liposome-coated nanocomplex targeting the liver in animal models. <h3>Methods</h3> We analyzed a tissue microarray of liver transplant samples from HCC patients (n = 259) to elucidate the correlation between FOXO1 expression and clinical parameters. We then constructed an esterase-responsive cationic liposome-coated nanocomplex carrying FOXO1, targeting the liver, and evaluated its effects in vivo on tumor recurrence post-transplant. <h3>Results</h3> Analysis of the liver transplant tissue microarray revealed that recipients with low FOXO1 expression had significantly shorter tumor-free survival (P = 0.010) and overall survival (P = 0.019) compared to those with high FOXO1 expression. Animal experiments showed that hepatic ischemia-reperfusion injury (IRI) induced changes in key inflammatory (TNF-α and IL-6) and oxidative stress proteins (Nrf-2 and HO-1), promoting tumor growth. Treatment with the liver-targeted FOXO1 esterase-responsive cationic liposome-coated nanocomplex significantly reduced tumor size in mice post-IRI compared to controls. Additionally, alanine aminotransferase and aspartate aminotransferase levels and liver histology (HE staining) indicated reduced IRI in treated mice. The nanocomplex treatment also decreased inflammatory protein expression and increased oxidative stress protein expression in the liver. <h3>Conclusion</h3> Low FOXO1 expression is a risk factor for post-transplant recurrence of HCC. FOXO1 can inhibit HCC progression by mitigating oxidative stress and inflammatory responses induced by hepatic IRI, providing a new strategy for the diagnosis and treatment of tumor recurrence after liver transplantation in HCC patients.