Amini Maral, Mokhtariye Armin, Mohammadalipour Adel, Hashemnia Mohammad, Mofid Mohammad Reza
Department of Clinical Biochemistry and Isfahan Pharmaceutical Sciences Research Center, Isfahan University of Medical Sciences, Isfahan, I.R. of Iran.
Department of Pathobiology, Faculty of Veterinary Medicine, Razi University, Kermanshah, Iran.
Mol Biol Rep. 2025 Aug 25;52(1):844. doi: 10.1007/s11033-025-10831-6.
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.
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.
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.
肝纤维化以导致肝硬化的进行性瘢痕形成为特征，是一项重大的全球健康负担。肝细胞凋亡推动纤维化发展，但其分子机制仍不清楚。本研究调查了IGFBP - 3/TMEM219通路在凋亡介导的肝纤维化进展中的作用。
通过胆管结扎（BDL）在35只雄性Wistar大鼠中诱导肝纤维化。五组（每组n = 7）包括对照组以及在BDL后7、14、21和28天处死的动物。使用RT - PCR、比色法和免疫荧光分析血清生物标志物（ALT、AST、ALP、胆红素）、组织病理学、基因表达（IGFBP - 3、TMEM219、HMOX1）和凋亡标志物（caspase 3/7、caspase 8）。ALT从对照组的52±4.3 U/L升至第28天的165±17.8 U/L（p < 0.001）。胶原面积从第7天的7.83±1.92%增加到第28天的43.20±2.46%。这些变化与IGFBP - 3和TMEM219基因表达的显著上调以及HMOX1表达的降低相对应。组织病理学分析显示，随着纤维化进展，肝损伤不断加重，包括胶原沉积增加。此外，caspase 3/7和caspase 8水平在各阶段均显著升高，表明凋亡途径被激活。
研究结果表明，IGFBP - 3/TMEM219通路在BDL诱导的大鼠模型中介导肝细胞凋亡和肝纤维化进展中起关键作用。凋亡标志物和纤维化相关基因表达的协同增加突出了该通路作为预防或减缓肝纤维化及其相关并发症的潜在治疗靶点。
