Energy Metabolic Reprogramming Characterized by Succinate Accumulation Aggravates Necrotizing Enterocolitis

Necrotizing enterocolitis (NEC) is a severe inflammatory intestinal disorder of preterm infants associated with substantial morbidity and mortality. This study investigated energy metabolic alterations in NEC and the contribution of succinate to disease progression. Fecal energy metabolites were quantified by high-performance liquid chromatography-mass spectrometry in preterm infants and neonatal mice. Neonatal C57BL/6 mice were assigned to the Control, NEC, NEC+dimethyl malonate (DMM), NEC+succinate (Suc), and NEC+DMM+Suc groups. Ileal tissues were analyzed by metabolomics, transcriptomics, histopathology, immunofluorescence, flow cytometry, Western blotting, reverse transcription quantitative PCR, and succinate dehydrogenase (SDH) activity assays. Both human neonates and neonatal mice with NEC exhibited metabolic reprogramming characterized by prominent succinate accumulation. Exogenous succinate further altered intestinal metabolism, reduced survival, aggravated weight loss and intestinal injury, decreased tight junction protein expression and lamina propria CD4⁺Foxp3⁺ regulatory T-cell proportions, and enhanced hypoxia-inducible factor-1α (HIF-1α)/interleukin-1β (IL-1β) signaling. Intestinal SDH activity and succinate dehydrogenase complex flavoprotein subunit A (SDHA) expression were increased in NEC and further enhanced by exogenous succinate, accompanied by increased colocalization of SDHA with F4/80⁺ macrophages. Pharmacological inhibition of SDH with DMM partially improved survival, intestinal injury, barrier disruption, and Treg loss, while suppressing HIF-1α/IL-1β signaling. These findings identify succinate accumulation as a metabolic hallmark of NEC and support a potential succinate-SDH-HIF-1α/IL-1β axis linking metabolic dysregulation to intestinal injury and immune imbalance.