2. Academic Validation
  3. Inhibiting sorting nexin 10 promotes mucosal healing through SREBP2-mediated stemness restoration of intestinal stem cells

Inhibiting sorting nexin 10 promotes mucosal healing through SREBP2-mediated stemness restoration of intestinal stem cells

  • Sci Adv. 2023 Sep;9(35):eadh5016. doi: 10.1126/sciadv.adh5016.
Weilian Bao 1 2,  Yan You 1,  Jiahui Ni 1,  Hui Hou 3,  Jiaren Lyu 1,  Guize Feng 1,  Yirui Wang 1,  Keyuan You 1,  Sulin Zhang 3,  Lijie Zhang 4,  Xinyue Cao 1,  Xu Wang 1,  Haidong Li 1,  Hong Li 1,  Jiake Xu 5 6,  Chenying Liu 7 8,  Xiaomin Luo 3,  Peng Du 7 8,  Daofeng Chen 2,  Xiaoyan Shen 1
Affiliations

Affiliations

  • 1 Department of Pharmacology and the Key Laboratory of Smart Drug Delivery Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China.
  • 2 Department of Natural Medicine, School of Pharmacy, Fudan University, Shanghai, China.
  • 3 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • 4 Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.
  • 5 School of Biomedical Sciences, University of Western Australia, Perth, WA, Australia.
  • 6 Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
  • 7 Department of Colorectal and Anal Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 8 Shanghai Colorectal Cancer Research Center, Shanghai, China.
PMID: 37647408 DOI: 10.1126/sciadv.adh5016
Abstract

Intestinal stem cell (ISC) is a promising therapeutic target for inflammatory bowel disease. Cholesterol availability is critical for ISC stemness. Low plasma Cholesterol is a typical feature of Crohn's disease (CD); however, its impact on mucosal healing remains unclear. Here, we identified an essential role of sorting nexin 10 (SNX10) in maintaining the stemness of ISCs. SNX10 expression in intestinal tissues positively correlates with the severity of human CD and mouse colitis. Conditional SNX10 knockout in intestinal epithelial cells or ISCs promotes intestinal mucosal repair by maintaining the ISC population associated with increased intracellular Cholesterol synthesis. Disassociation of ERLIN2 with SCAP by SNX10 deletion enhances the activation of SREBP2, resulting in increased Cholesterol biosynthesis. DC-SX029, a small-molecule inhibitor of SNX10, was used to verify the druggable potential of SNX10 for the treatment of patients with CD. Our study provides a strategy for mucosal healing through SREBP2-mediated stemness restoration of ISCs.

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