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Updated: Aug 22, 2025
Murine Colitis Modeling using Dextran Sulfate Sodium DSS
Published on: January 19, 2010
A novel gut-restricted RIPK1 inhibitor, SZ-15, ameliorates DSS-induced ulcerative colitis
Yi-Sheng Zeng1, Jian Peng1, Xiao-Fang Gao1
1School of Pharmacy, Chengdu Medical College, No. 783, Xindu Avenue, Xindu District, Chengdu, Sichuan Province, 610500, China.
Abstract:
As a key mediator of cell death and inflammation, receptor-interacting protein kinase 1 (RIPK1) responds to a broad set of inflammatory and pro-death stimuli in human diseases. Inhibitors targeting RIPK1 are being investigated for the treatment of a wide range of human diseases, including ulcerative colitis. In the present study, we designed, synthesized, and investigated the anti-necroptosis and RIPK1-inhibition effects of SZ-15-a symmetrical high-molecular-weight (>500 Da) compound. SZ-15 effectively inhibited necroptosis in U937 and HT-29 cells at concentrations of 1 nM and 10 nM, respectively, and SZ-15 at a concentration of 10 nM almost completely blocked RIPK1, RIPK3, and mixed-lineage kinase domain-like (MLKL) protein phosphorylation induced by necrosis inducers. SZ-15 suppressed the pro-necroptosis function of RIPK1 by downregulating the mRNA expression of pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6. The activities of SZ-15 were effectively restricted to the gut: The percent recovery of the parent form of SZ-15 in mouse feces was 85.75%. Nevertheless, SZ-15 was effectively absorbed and detected in colon tissues after 1 h at a concentration of 3335 ± 868 ng/g, indicating that membrane permeability was maintained. SZ-15 alleviated dextran sulfate sodium (DSS)-induced ulcerative colitis in vivo by decreasing TNF-α, IL-1β, IL-22, and IL-6 mRNA expression in colonic tissues. Our preclinical study describes a novel gut-restricted RIPK1 inhibitor that shows great potential for use in the clinical treatment of ulcerative colitis.
Insights
A novel gut-restricted inhibitor, SZ-15, effectively blocks receptor-interacting protein kinase 1 (RIPK1) and necroptosis. This compound shows promise for treating ulcerative colitis by reducing inflammation in the gut.
Area of Science:
- Biochemistry
- Immunology
- Pharmacology
Background:
- Receptor-interacting protein kinase 1 (RIPK1) is a key mediator of cell death and inflammation implicated in various human diseases.
- RIPK1 inhibitors are under investigation for treating inflammatory conditions, including ulcerative colitis.
- Developing targeted therapies with localized activity is crucial for managing gut-specific diseases.
Purpose of the Study:
- To design, synthesize, and evaluate the anti-necroptosis and RIPK1-inhibiting effects of a novel compound, SZ-15.
- To assess the gut-restricted activity and therapeutic potential of SZ-15 in a preclinical model of ulcerative colitis.
Main Methods:
- SZ-15's inhibition of necroptosis and RIPK1, RIPK3, and MLKL phosphorylation was tested in U937 and HT-29 cells.
- The compound's effect on pro-inflammatory cytokine mRNA expression (TNF-α, IL-1β, IL-6) was analyzed.
- Gut-restricted activity was confirmed by recovery in mouse feces and detection in colon tissues.
- Efficacy was evaluated in a dextran sulfate sodium (DSS)-induced ulcerative colitis mouse model.
Main Results:
- SZ-15 potently inhibited necroptosis in cell lines at nanomolar concentrations.
- The compound significantly blocked RIPK1, RIPK3, and MLKL phosphorylation.
- SZ-15 demonstrated gut-restricted activity with high recovery in feces and absorption in colon tissue.
- In vivo, SZ-15 alleviated DSS-induced ulcerative colitis by reducing key inflammatory cytokine mRNA levels in the colon.
Conclusions:
- SZ-15 is a novel, high-molecular-weight, gut-restricted RIPK1 inhibitor.
- The compound effectively suppresses necroptosis and inflammation.
- SZ-15 shows significant therapeutic potential for the clinical treatment of ulcerative colitis.
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