REDD1 attenuates cholestatic liver fibrosis and suppresses PI3K/AKT/mTOR pathway

Introduction Liver fibrosis is reversible. Cholestasis is an important factor causing liver fibrosis. However, there are currently no effective anti-fibrotic drugs for cholestatic liver fibrosis in clinical practice. Methods mRNA sequencing was performed using mouse bile duct ligation (BDL) of liver tissue, and RT-qPCR was used to screen for the target gene REDD1. Immunohistochemistry was used to detect the expression of REDD1, CD68, α-SMA, and PI3K/AKT/mTOR signaling pathways in primary biliary cholangitis (PBC) patient liver tissue. Subsequently, adenovirus mediated REDD1 was transfected into mouse liver tissue via tail vein to evaluate its therapeutic effect. Results RNA sequencing revealed REDD1 was significantly upregulated in BDL-induced fibrotic liver tissue. REDD1 expression correlated positively with α-SMA and CD68 in PBC patients, suggesting its involvement in fibrogenesis. However, REDD1 overexpression ameliorated BDL-induced liver injury, reduced serum ALT/AST levels, and decreased collagen deposition, as evidenced by histological and molecular analyses (α-SMA and collagen I), indicating that REDD1 exhibited compensatory elevation in liver fibrosis. Additionally, PI3K/AKT/mTOR pathway was involved in the improvement of liver fibrosis by REDD1. Conclusions These findings highlight REDD1 as a potential therapeutic target for liver fibrosis, acting probably through modulation of the PI3K/AKT/mTOR pathway to mitigate fibrotic processes.