Mokhtariye Armin, Varshosaz Jaleh, 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. Iran.
Novel Drug Delivery Systems Research Centre, Department of Pharmaceutics, School of Pharmacy, Isfahan University of Medical Sciences, Isfahan, Iran.
Life Sci. 2025 Sep 15;377:123748. doi: 10.1016/j.lfs.2025.123748. Epub 2025 May 28.
Insulin-like growth factor binding protein-3 (IGFBP-3) activates hepatic stellate cells, enhancing hepatic fibrogenesis. This research aimed to fabricate IGFBP-3 targeted xanthosomes loaded with transmembrane-protein 219 (TMEM219) to target TGFβ/IGFBP-3 signaling pathway in liver fibrosis.
Recombinant TMEM219 was expressed, purified, and loaded into xanthosomes using thin-film hydration method. MTT assay performed cytotoxicity on the LX-2 cell line. Liver fibrosis was induced in rats via bile duct ligation, followed by intravenous injection: Sham (SH) and Fibrotic (F) with saline, Short-term (ST) and Long-term (LT) TMEM219 loaded in targeted xanthosomes (0.4 mg/kg), Blank targeted xanthosomes (BST and BLT), and free TMEM219 (Free; 0.4 mg/kg). Evaluations included biochemical parameters, histopathology and immunohistochemistry, α-SMA and COL1A1 mRNA expression, serum IGFBP-3 levels, and TGF-β1 protein expression.
TMEM219-loaded xanthosomes exhibited a particle size of 149.9 nm, zeta-potential of -11.4 mV, and loading efficiency of 71.5 %. MTT assay showed lower cytotoxicity of targeted xanthosomes compared to free TMEM219 (p < 0.05). ST and LT groups significantly improved AST and ALT levels, histopathology (reduced necrosis, fibrogenesis, inflammation), α-SMA and COL1A1 expression, serum IGFBP-3, p-AKT and TGF-β1 expression (p < 0.05, p < 0.01).
Improvements in therapeutic parameters indicated reduced liver fibrosis progression. This study demonstrates that TMEM219-xanthosomes effectively target IGFBP-3, significantly reducing liver fibrosis.
胰岛素样生长因子结合蛋白-3（IGFBP-3）可激活肝星状细胞，增强肝纤维化形成。本研究旨在制备负载跨膜蛋白219（TMEM219）的IGFBP-3靶向黄嘌呤体，以靶向肝纤维化中的TGFβ/IGFBP-3信号通路。
表达、纯化重组TMEM219，并采用薄膜水化法将其载入黄嘌呤体。MTT法检测对LX-2细胞系的细胞毒性。通过胆管结扎诱导大鼠肝纤维化，随后静脉注射：假手术组（SH）和纤维化组（F）注射生理盐水，短期组（ST）和长期组（LT）注射负载于靶向黄嘌呤体中的TMEM219（0.4mg/kg）、空白靶向黄嘌呤体（BST和BLT）以及游离TMEM219（游离；0.4mg/kg）。评估指标包括生化参数、组织病理学和免疫组织化学、α-SMA和COL1A1 mRNA表达、血清IGFBP-3水平以及TGF-β1蛋白表达。
负载TMEM219的黄嘌呤体粒径为149.9nm，ζ电位为-11.4mV，负载效率为71.5%。MTT法显示，与游离TMEM219相比，靶向黄嘌呤体的细胞毒性更低（p<0.05）。短期组和长期组显著改善了AST和ALT水平、组织病理学（坏死、纤维化形成、炎症减轻）、α-SMA和COL1A1表达、血清IGFBP-3、p-AKT和TGF-β1表达（p<0.05，p<0.01）。
治疗参数的改善表明肝纤维化进展减缓。本研究表明，TMEM219-黄嘌呤体能有效靶向IGFBP-3，显著减轻肝纤维化。
