非酒精性脂肪性肝炎（NASH）相关肝纤维化是NASH向肝硬化、肝癌进展的独立危险因素。然而，其精确分子机制仍不清楚。研究发现，Kupffer细胞和肝星状细胞（HSCs）激活参与NASH相关肝纤维化进展，且二者之间具有一定的相关性。同时，HSC自噬发生可直接导致HSC激活。预实验中我们发现，用脂多糖（LPS）激活Kupffer 细胞，可诱导Toll样受体4和Dll4表达水平上调。因此，我们提出：在NASH发生发展过程中，肠道来源LPS或损伤相关分子模式（DAMPs）等因素激活Kupffer细胞，促使Dll4表达上调，并激活HSC内Notch信号诱导HSC自噬发生，导致HSC激活，进而促进NASH相关肝纤维化发生。为此，本课题组拟从临床、细胞和动物实验水平阐明这一机制。无疑，这将为NASH相关肝纤维化的临床防治提供新的治疗策略和干预靶点。

Non-alcoholic steatohepatitis (NASH) related liver fibrosis is the independent risk factor of liver cirrhosis and liver cancer. However, the precise molecular mechanism remains unclear.Previous evidence suggests, Kupffer cells and hepatic stellate cells (HSCs) activation were involved NASH related liver fibrosis progression, and there is a certain correlation between them, but how to contact is not clear. Mean while, the HSCs autophagy can result in HSC activation. Further，our preliminary data showed that the expressions of Toll-like receptors (TLRs) and Delta-like 4 (Dll4) were upregulated on the cell surface of lipopolysaccharide (LPS)-stimulated Kupffer cells. Based on these data, we hypothesized that during NASH progression, the intestinal LPS or damaged-associated molecular pattern（DAMPs）activated Kupffer cells by TLR4-mediated signaling pathway, inducing the expression of Dll4, triggering HSC autophagy by activating Notch signaling in HSC, causing HSC activation and further promote NASH related liver fibrosis. We plan to explore the underlying mechanisms from clinical, cellular to animal experiments. No doubt, this project may provide novel target for NASH related liver fibrosis treatment.