Necrotizing enterocolitis is exacerbated through SUCNR1/HIF-1α/BNIP3 axis-mediated succinate-induced intestinal...

To elucidate the mechanism by which succinate exacerbates intestinal injury in necrotizing enterocolitis (NEC).

Succinate levels were measured in newborns and mice with NEC. Intestinal epithelial damage and apoptosis were evaluated in NEC models. The expression of succinate receptor 1 (SUCNR1), hypoxia-inducible factor 1-alpha (HIF-1α), and BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3) was inhibited, and the associated pathway proteins were quantified. The regulatory relationship between HIF-1α and BNIP3 was elucidated using ChIP‒qPCR and dual-luciferase reporter gene assays.

Compared with those in the control group, succinate levels were elevated in the feces of NEC neonates and the intestinal tissue of NEC mice. Succinate treatment exacerbated intestinal epithelial damage, increasing Bax and cleaved caspase-3 expression, as well as the cleaved caspase-9 to pro-caspase-9 ratio, while downregulating Bcl-2 expression. Additionally, succinate increased mitochondrial membrane potential depolarization and cytochrome c (Cyt c) efflux in NEC cell models. The inhibition of SUCNR1, HIF-1α, or BNIP3 may mitigate intestinal epithelial cell apoptosis (P < 0.05). HIF-1α regulated BNIP3 expression, as shown by ChIP‒qPCR and dual luciferase assays.

Succinate may exacerbate the apoptosis of intestinal epithelial cells in an NEC model through the SUCNR1/HIF-1α/BNIP3 pathway.

The pathogenesis of NEC remains incompletely understood; however, elevated succinate levels are recognized as an important contributor to its development and progression. Succinate intervention exacerbated intestinal epithelial damage and intestinal epithelial cell apoptosis in the NEC model through the SUCNR1/HIF-1α/BNIP3 pathway. Succinate may serve not only as a potential therapeutic target but also as a novel biomarker for early diagnosis and disease monitoring of NEC. Additionally, future research should focus on integrating microbial-metabolite interaction analyses, advancing the clinical application of metabolic interventions, and improving the prognosis of NEC infants.