Stage-specific role of IGFBP-3/TMEM219 pathway in liver fibrosis progression using a bile duct ligation rat model

Abstract

Background: Liver fibrosis, characterized by progressive scarring leading to cirrhosis, represents a major global health burden. Hepatocyte apoptosis drives fibrosis development, yet the molecular mechanisms remain unclear. This study investigates the role of the IGFBP-3/TMEM219 pathway in apoptosis-mediated liver fibrosis progression. Methods and results: Liver fibrosis was induced in 35 male Wistar rats via bile duct ligation (BDL). Five groups (n = 7 each) included controls and animals sacrificed at 7, 14, 21, and 28 days post-BDL. Serum biomarkers (ALT, AST, ALP, bilirubin), histopathology, gene expression (IGFBP-3, TMEM219, HMOX1), and apoptotic markers (caspase 3/7, caspase 8) were analyzed using RT-PCR, colorimetry, and immunofluorescence. ALT rose from 52 +/- 4.3 U/L in controls to 165 +/- 17.8 U/L at day 28 (p < 0.001). Collagen area increased from 7.83 +/- 1.92 (day 7) to 43.20 +/- 2.46 (day 28). These changes corresponded with a significant upregulation of IGFBP-3 and TMEM219 gene expression, alongside a decrease in HMOX1 expression. Histopathological analysis revealed advancing liver damage, including increased collagen deposition, as fibrosis progressed. Additionally, levels of caspase 3/7 and caspase 8 rose significantly across stages, indicating activation of apoptotic pathways. Conclusion: The findings demonstrate that the IGFBP-3/TMEM219 pathway plays a crucial role in mediating hepatocyte apoptosis and the progression of liver fibrosis in the BDL-induced rat model. The coordinated increase in apoptotic markers and fibrosis-associated gene expression highlights this pathway as a potential therapeutic target for preventing or slowing liver fibrosis and its related complications.