靶向TRIB3/p62相互作用抑制肝纤维化的作用和机制

Hepatic fibrosis, the core pathological changes in the initiation and development of chronic liver diseases, is threatening the public healthy in China. Our preliminary studies indicate that inhibiting the chronic inflammatory reponses around the fibrotic focus and subsequently recovering the suppressed autophagy is the potential way to cure the fibroproliferative diseases, such as pulmonary and hepatic fibrosis. We have recently found that IL-17A particpates in hepatic fibrosis through inhibiting the activation of autophagy, and IL-17A-enhanced TRIB3, a stress-induced protein, could be a key mediator in the pathogenesis of hepatic fibrosis. Moreover, we identified that TRIB3 interacts with the autophagic receptor p62 and caused its accumulation is a crucial mechanism in the process of autophagy suppression. Accumulated evidences have revealed that autophagy is essential pathway for the degradation of multive vesicles bodies (MVBs) in hepatocytes and autophagy suppression could be involved in the secretion of exosomes from MVBs, the released exosomes can further contribute to the development of hepatic fibrosis through activating hepatic stellate cells (HSCs). We therefore hypothesize that 1) the TRIB3-p62 interaction mediates the development and progression of hepatic fibrosis via suppressing autophagic degradation of MVBs and promoting the secretion of hepatocellular exosomes which can further activate the HSCs, 2) targeting TRIB3-p62 interaction would have therapeutic benefits against the hepatic fibrosis. To prove this hypothesis, we will pursuit the potential roles and mechanisms of TRIB3-mediated autophagy suppression in the pathogenesis of hepatic fibrosis, and explore the therapeutic strategy for the treatment of hepatic fibrosis. Our proposed studies may not only provide deep insights into the pathogenesis of hepatic fibrosis but also provide clues and opportunities for the development of anti-hepatic fibrosis drugs.

肝纤维化严重威胁我国人民生命健康，是慢性肝病发生发展的核心病理改变。我们前期研究表明通过抑制病灶局部慢性炎症并恢复细胞自噬，是改善肺和肝脏等多种组织纤维化的重要途径。本课题组发现IL-17A抑制肝细胞自噬参与肝纤维化的发病，其机制与IL-17A调控应激蛋白TRIB3高表达有关。此外，我们还证明TRIB3与自噬受体蛋白p62相互作用是抑制自噬系统的关键机制。另有研究表明肝细胞多泡体的自噬性降解受阻后向胞外释放外体，通过激活星形细胞参与肝纤维化发病。因此我们提出假说：1）TRIB3/p62相互作用抑制肝细胞中多泡体的自噬性降解促进外体分泌并激活肝纤维化关键效应器细胞-星形细胞；2）靶向TRIB3/p62相互作用能够抑制肝纤维化的发生发展。我们将在整体动物-细胞-分子三个层次，阐明TRIB3介导自噬抑制在肝纤维化发病中的机制，鉴定抗肝纤维化药物的新靶点，为开发新一代肝纤维化防治药物提供新的思路。

肝纤维化是多种慢性肝病的核心病理改变，细胞自噬功能异常在肝纤维化发病过程中发挥关键作用。我们发现在肝纤维化发病过程中，TRIB3与自噬底物受体p62相互作用是阻碍肝细胞晚期内体发生自噬性降解的关键机制，导致其向胞外释放大量促进肝星形细胞活化的富含INHBA的外泌体，进而参与肝纤维化发病。使用能打断TRIB3-p62相互作用的穿膜肽可以有效恢复肝细胞自噬流从而逆转肝纤维化的发病。该研究重点解析了TRIB3在肝组织损伤-自噬-肝纤维化中的关键连接作用和机制，为肝纤维化的治疗提供了新的诊疗策略、药物靶点及先导多肽。作为上述工作的延续，我们将自噬阻滞的思路拓展到心脏组织纤维增生性疾病中，从蛋白稳态角度加深了对组织纤维化疾病发病机制的认识。发现先天免疫受体TLR2与细胞外关键损伤相关模式分子HMGB1和HSP70间的相互作用是抑制成纤维细胞自噬、诱导心肌炎症参与心肌纤维化的关键机制，而HMGB1特异性拮抗剂甘草酸及HSP70中和性抗体可明显抑制心脏纤维化进展，该研究也为纤维增生性心脏病的治疗提供了潜在靶点和候选药物。