Nicotinamide riboside reduced radiation-induced intestinal injury in experimental models by -dependent inhibition of GSDME-mediated .
Evidence
This preclinical study used irradiated mice, intestinal epithelial cell-specific Gsdme-deficient mice, organoids, and intestinal cell lines, with supporting marker comparisons in radiation-injured colorectal mucosa from patients after radiotherapy.
Caveat
The therapeutic evidence is mainly from animal, organoid, and cell models, while the human samples support pathway relevance rather than clinical treatment efficacy.
Simplified
INTRODUCTION: Radiation-induced intestinal injury (IR) is a common complication in patients with colorectal cancer (CRC) after radiotherapy. Currently, the search for effective treatments has become an urgent priority. Nicotinamide riboside (NR), the precursor of vitamin B3 derivative and NAD (+), was enriched in IR after treatment with commensal Bacteroides fragilis, suggesting that NR may perform a protective role. However, the specific role of NR in IR remains unclear. In this study, we investigated the therapeutic effects of NR on IR.
METHODS: C57BL/6J, Gsdme(lacking GSDME in intestinal epithelial cells, IECs), and wild-type littermates were treated with NR after abdominal radiation exposure at 10 Gy. The small intestinal crypt-derived organoids and cell lines FHC, NCM460, and IEC-6 were irradiated with or without administration of the inhibitor EX527 under NR stimulation. A series of assays were subsequently carried out to explore the therapeutic effects, the degree of IECs repair, and the underlying mechanism. ΔIEC
RESULTS: NR significantly ameliorated IR in mice, as evidenced by reduced weight loss, shortened small intestinal and colonic length, improved histological associated index, and restored the intestinal flora, which increased the relative abundance of the commensal Muribaculaceae, and decreased the relative abundance of Escherichia_coli. Additionally, NR increased goblet cell density, increased crypt length, promoted Ki-67 and ZO-1 expression, reduced reactive oxygen species (ROS) levels, and maintained mitochondrial morphology in IECs. Mechanistically, NR activated SIRT1 and inhibited gasdermin E (GSDME)-induced . Further investigations using an experimental Gsdmemouse model (lacking GSDME in IECs) and a SIRT1 inhibitor revealed that NR promoted intestinal barrier repair through GSDME inhibition in a SIRT1-dependent manner. Compared with those in healthy controls, the GSDME level in radiation-injured colorectal mucosa from CRC patients after radiotherapy increased with the downregulation of SIRT1, Ki-67, and ZO-1. ΔIEC
CONCLUSION: Our study demonstrated that NR mitigates IR by inhibiting GSDME-mediated pyroptosis and restoring IECs homeostasis. These findings suggest that NR could serve as a promising therapeutic strategy for IR following radiotherapy.
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