非酒精性脂肪肝病（NAFLD）因其高发病率、趋向恶性的发展趋势以及缺乏有效治疗，成为全球面临的健康问题。持续性NAFLD会使患者从单纯的脂肪肝病变发展成肝炎，肝纤维化直至肝癌。目前研究表明自噬对于NAFLD以及肝细胞癌（HCC）的发展具有直接作用，但调控机制尚不完全清楚。我们已发表工作揭示了泛素连接酶Smurfs 通过促进Hedgehog（Hh）受体Ptch1内吞清除而调控其出原纤毛，促进Hh信号转导。我们前期工作还显示Smurf1基因敲除小鼠自发呈现NAFLD症状，Smurf1和Hh在肝细胞模型中促进自噬。这些结果提示Smurf1参与肝细胞的自噬调控。本研究旨在系统阐明Hh-Smurf1通路调节自噬的分子机理，揭示调节功能异常在NAFLD和相关HCC的重要意义，揭示由自噬调节紊乱造成NAFLD的新分子机制。该机制的解析将为定位NAFLD高危患者，进而采取靶向性生物治疗开辟新途径。

Non-alcoholic fatty liver disease (NAFLD) has emerged as a major unmet medical challenge because of its prevalence, dire clinical complication and lack of effective therapies. Sustained NAFLD conditions can progress from simple hepatic steatosis to non-alcoholic steatohepatitis (NASH) and liver cirrhosis, and ultimately to liver cancer. Mounting evidence has implicated the importance of autophagy in the progression of NAFLD to liver cancers, but the regulatory mechanisms are not completely understood. Our published work has demonstrated that HECT-domain E3 ligases Smurf1 and Smurf2 regulate the endocytic clearance of Hedgehog receptor Ptch1 from primary cilia, thus playing a positive role in Hedgehog signaling. We also observed that Smurf1 null mice, which are grossly normal, nevertheless develop NAFLD as they age. Here in this proposed research, we will delineate the pathway by which Hedgehog-Smurfs signaling axis regulates autophagy and elucidate the significance of this mechanism in NAFLD progression and its impact on liver cancer.