2. Academic Validation
  3. PROTAC based STING degrader attenuates acute colitis by inhibiting macrophage M1 polarization and intestinal epithelial cells pyroptosis mediated by STING-NLRP3 axis

PROTAC based STING degrader attenuates acute colitis by inhibiting macrophage M1 polarization and intestinal epithelial cells pyroptosis mediated by STING-NLRP3 axis

  • Int Immunopharmacol. 2024 Nov 15:141:112990. doi: 10.1016/j.intimp.2024.112990.
Shuai Xu 1,  Yifeng Peng 1,  Kai Yang 1,  Sheng Liu 1,  Zhanke He 1,  Junli Huang 2,  Ruipei Xiao 1,  Jin Liu 3,  Ziyan Yan 1,  Zhiying Lian 1,  Huayang Pan 1,  Jianjun Chen 4,  Jiaolong Shi 5,  Xingxing Yao 6,  Haijun Deng 7
Affiliations

Affiliations

  • 1 Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Guangzhou, Guangdong, China.
  • 2 Department of Pharmacy, The People's Hospital of Guangxi Zhuang Autonomous Region & Guangxi Academy of Medical Sciences, Nanning, Guangxi 530021, China.
  • 3 Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China.
  • 4 School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou 510515, China.
  • 5 Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Guangzhou, Guangdong, China. Electronic address: shijiaolong10@smu.edu.cn.
  • 6 Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Guangzhou, Guangdong, China. Electronic address: mhyxx88@163.com.
  • 7 Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Guangzhou, Guangdong, China. Electronic address: navyd999@163.com.
PMID: 39223062 DOI: 10.1016/j.intimp.2024.112990
Abstract

Inflammatory bowel diseases (IBDs) are chronic, relapsing, and inflammatory disorders of the gastrointestinal tract characterized by abnormal immune responses. Recently, STING has emerged as a promising therapeutic target for various autoinflammatory diseases. However, few STING-selective small molecules have been investigated as novel strategies for IBD. In this study, we sought to examine the effects of PROTAC-based STING degrader SP23 on acute colitis and explore its underlying mechanism. SP23 treatment notably alleviates dextran sulfate sodium (DSS)-induced colitis. Pharmacological degradation of STING significantly reduced the production of inflammatory cytokines, such as TNF-α, IL-1β, and IL-6, and inhibited macrophage polarization towards the M1 type. Furthermore, SP23 administration decreased the loss of tight junction proteins, including ZO-1, occludin, and claudin-1, and downregulated STING and NLRP3 signaling pathways in intestinal inflammation. In vitro, STING activated NLRP3 inflammasome-mediated Pyroptosis in intestinal epithelial cells, which could be abrogated by SP23 and STING siRNA intervention. In conclusion, these findings provide new evidence for STING as a novel therapeutic target for IBD, and reveal that hyperactivation of STING could exaggerate colitis by inducing NLRP3/Caspase-1/GSDMD axis mediated intestinal epithelial cells Pyroptosis.

Keywords

Inflammatory bowel disease; M1 macrophage; NLRP3; STING PROTAC degrader; Tight junction protein.

Figures
Products