Barrett食管的发病率在我国逐年递增，且不少于90%的食管腺癌由其演变而来。当前药物无法逆转化生到癌变的进展，而手术治疗创伤大、风险高，探究治疗新靶标是解决此临床困境的关键。我们的前期工作利用组织样本分析，结合分子实验，证实了MTHFD1L在Barrett食管中表达增高并调控化生演变，又通过转录组学分析和蛋白-蛋白互作的多层次筛选，发掘了MTHFD1L的互作蛋白SIRT3。进一步研究发现，MTHFD1L调控SIRT3蛋白的SUMO化修饰，激活SIRT3促进线粒体自噬，参与介导Barrett食管的化生演变。在此基础上，本项目将在细胞、动物及人体模型多个层面系统研究MTHFD1L靶向SIRT3调控线粒体自噬的分子作用机制，深入揭示MTHFD1L-SIRT3-线粒体自噬介导Barrett食管化生演变的功能作用，明确MTHFD1L作为治疗靶标的潜在价值，为下一步的临床转化研究提供科学理论依据。

Barrett's esophagus is a premalignant condition of esophageal adenocarcinoma, and its incidence has risen rapidly in China. However, the molecular pathogenesis of Barrett’s esophagus remains unclear. Our previous study has indicated that MTHFD1L, a core enzyme of folate metabolism pathway, is involved in the development of ESCC. However, its role in the Barrett’s esophagus is still unknown, and our study showed that MTHFD1L protein and RNA expression levels were significantly upregulated in the tissue of Barrett’s esophagus as compared with normal tissue. Knockdown of MTHFD1L expression regress the Barrett's metaplasia that is mediated through mitophagy. Our further investigation showed that the MTHFD1L-induced mitophagy was dependent on its interaction with SIRT3. Meanwhile, this study highlighted that the SUMOylation of SIRT3 was regulated by MTHFD1L. In this research project, we will investigate the molecular mechanism of MTHFD1L/SIRT3/mitophagy signaling axis in the process of Barrett metaplasia via in vivo and in vitro arrays. Also, an ideal gastroesophageal reflux human cohort study will help to determine the potential clinical value of MTHFD1L for the early diagnosis of Barrett’s esophagus. These studies will provide foundations for functional study of MTHFD1L in Barrett’s esophagus diseases and further development of related treatment strategies for the regression of Barrett's esophagus.