Roseotoxin B alleviates cholestatic liver fibrosis through inhibiting PDGF-B/PDGFR-β pathway in hepatic stellate cells
Roseotoxin B alleviates cholestatic liver fibrosis through inhibiting PDGF-B/PDGFR-β pathway in hepatic stellate cells
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Roseotoxin B 通过抑制肝星状细胞中的 PDGF-B/PDGFR-β 途径减轻胆汁淤积性肝纤维化
DOI：
10.1038/s41419-020-2575-0
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发表时间：
2020-06-15
影响因子：
9
通讯作者：
Yao, Ruiqin
中科院分区：
文献类型：
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作者：
Wang, Xingqi;Gao, Yuzhi;Yao, Ruiqin
确定有效的抗纤维化疗法是仍未满足的主要临床需求。在本研究中，玫瑰毒素B具有改善胆管结扎小鼠胆汁淤积性肝纤维化的作用，通过组织化学和免疫组织化学染色，肝生化参数，并在组织切片中的TUNEL凋亡细胞检测证明。利用细胞热位移分析、计算分子对接、微尺度热泳技术和表面等离子体共振生物传感器，我们证实PDGFR-β是纤维化肝脏中玫瑰毒素B的直接靶点。值得注意的是，人类组织微阵列在类似于80%的肝纤维化和肝硬化患者的肝脏样品中检测到p-PDGFR-β的病理高表达。PDGF-B/PDGFR-beta通路促进肝星状细胞（HSC）的转分化和过度增殖，这是肝纤维化的一个非常关键的驱动因素。有意义的是，玫瑰毒素B通过靶向PDGFR-β的D2结构域阻断PDGF-BB/PDGFR-β β复合物的形成，从而抑制HSC中的PDGF-B/PDGFR-β通路。总之，我们的研究提供了玫瑰毒素B作为一个独特的候选药物治疗肝纤维化。
Identifying effective anti-fibrotic therapies is a major clinical need that remains unmet. In the present study, roseotoxin B was shown to possess an improving effect on cholestatic liver fibrosis in bile duct-ligated mice, as proved by histochemical and immunohistochemical staining, hepatic biochemical parameters, and TUNEL apoptotic cell detection in tissue sections. Using cellular thermal shift assay, computational molecular docking, microscale thermophoresis technology, and surface plasmon resonance biosensor, we confirmed that PDGFR-beta was a direct target of roseotoxin B in fibrotic livers. Of note, human tissue microarrays detected pathologically high expression of p-PDGFR-beta in liver samples of similar to 80% of patients with liver fibrosis and cirrhosis. PDGF-B/PDGFR-beta pathway promotes transdifferentiation and excessive proliferation of hepatic stellate cells (HSCs), which is a very crucial driver for liver fibrosis. Meaningfully, roseotoxin B blocked the formation of PDGF-BB/PDGFR-beta beta complex by targeting the D2 domain of PDGFR-beta, thereby inhibiting the PDGF-B/PDGFR-beta pathway in HSCs. In summary, our study provided roseotoxin B as a unique candidate agent for the treatment of liver fibrosis.