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J. Mol. Sci.","IJMS"],"abstract":"<jats:p>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\u2013mass 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-1\u03b1 (HIF-1\u03b1)\/interleukin-1\u03b2 (IL-1\u03b2) 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-1\u03b1\/IL-1\u03b2 signaling. These findings identify succinate accumulation as a metabolic hallmark of NEC and support a potential succinate\u2013SDH\u2013HIF-1\u03b1\/IL-1\u03b2 axis linking metabolic dysregulation to intestinal injury and immune imbalance.<\/jats:p>","DOI":"10.3390\/ijms27198691","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T09:10:54Z","timestamp":1790673054000},"page":"8691","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Energy Metabolic Reprogramming Characterized by Succinate Accumulation Aggravates Necrotizing Enterocolitis"],"prefix":"10.3390","volume":"27","author":[{"given":"Xiao-Lin","family":"Yan","sequence":"first","affiliation":[{"name":"Department of Neonatology, Children\u2019s Hospital of Chongqing Medical University, National Clinical Research Center for Children and Adolescents\u2019 Health and Diseases, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Chongqing 400014, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"}]},{"given":"Yu","family":"He","sequence":"additional","affiliation":[{"name":"Department of Neonatology, Children\u2019s Hospital of Chongqing Medical University, National Clinical Research Center for Children and Adolescents\u2019 Health and Diseases, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Chongqing 400014, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]},{"given":"Xiao-Chen","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Neonatology, Children\u2019s Hospital of Chongqing Medical University, National Clinical Research Center for Children and Adolescents\u2019 Health and Diseases, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Chongqing 400014, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Yu-Ni","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neonatology, Children\u2019s Hospital of Chongqing Medical University, National Clinical Research Center for Children and Adolescents\u2019 Health and Diseases, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Chongqing 400014, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Fang-Ling","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Neonatology, Children\u2019s Hospital of Chongqing Medical University, National Clinical Research Center for Children and Adolescents\u2019 Health and Diseases, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Chongqing 400014, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Lei","family":"Bao","sequence":"additional","affiliation":[{"name":"Department of Neonatology, Children\u2019s Hospital of Chongqing Medical University, National Clinical Research Center for Children and Adolescents\u2019 Health and Diseases, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Chongqing 400014, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4571-4424","authenticated-orcid":false,"given":"Yuan","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Neonatology, Children\u2019s Hospital of Chongqing Medical University, National Clinical Research Center for Children and Adolescents\u2019 Health and Diseases, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing 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