陆军军医大学学报2026，Vol.48Issue(11)：1505-1517,13.DOI:10.16016/j.2097-0927.202602104
NUPR1下调介导巨噬细胞氧化磷酸化损伤参与溃疡性结肠炎发病
NUPR1 downregulation-mediated impairment of macrophage oxidative phosphorylation participates in the pathogenesis of ulcerative colitis
摘要
Abstract
Objective Macrophages are key cellular contributors to the development and progression of ulcerative colitis(UC),and their functional state is closely related to oxidative phosphorylation(OXPHOS)capacity.However,changes in macrophage OXPHOS levels in UC patients remain unclear.This study aims to evaluate macrophage OXPHOS capacity in colonic tissues of UC patients and to identify and validate key regulatory genes.Methods Five colonic scRNA-seq datasets from UC cohorts were integrated,comprising 54 samples in total,including 18 healthy controls(HC)and 36 UC cases.After clustering and cell annotation,analyses were focused mainly on monocyte and macrophage subsets.Five gene set scoring algorithms,including AUCell,UCell,singscore,ssGSEA,and JASMINE,were used to calculate OXPHOS scores in these 2 cell types.Robust rank aggregation(RRA)was employed to compare the OXPHOS scores of monocyte and macrophage subsets between HC and UC cells.Candidate regulatory genes were identified by intersecting hub genes with differentially expressed genes(DEGs).Male C57BL/6N mice(10 to 12 weeks old,weighing 25±2 g)were randomly assigned to a DSS-induced acute colitis group(n=6)or a CTR group(n=8).Immunofluorescence assay was utilized to detect nuclear protein 1,transcriptional regulator(NUPR1)expression in colonic macrophages.After siRNA-mediated knockdown of Nupr1 in mouse primary bone marrow-derived macrophages(BMDMs),the ATP levels were measured.Pseudotime analysis and virtual knockout were further performed to explore potential mechanisms.Results Compared with the HC group,the UC group exhibited an increased proportion of myeloid cells,with an increase in monocytes and a decrease in macrophages.OXPHOS pathway scores were significantly reduced in macrophages(P＜0.05),whereas no obvious change was observed in monocytes.Nineteen OXPHOS hub genes were identified(P＜0.05),and intersection with macrophage DEGs yielded NUPR1 as a key candidate gene.NUPR1 was significantly downregulated in macrophages from UC patients(adj.P＜0.001)and in colonic macrophages from DSS-induced colitis mice.After siRNA-mediated knockdown of Nupr1 in BMDMs(P＜0.05),the fluorescence intensity of TOM20 was decreased(P＜0.001).ATP levels in BMDMs were significantly reduced after Nupr1 knockdown(P＜0.01)and LPS stimulation(P＜0.001),and the combined treatment had a stronger effect than either Nupr1 knockdown(P＜0.01)or LPS stimulation alone(P＜0.05).Pseudotime analysis showed that NUPR1 expression was gradually decreased with pseudotime,consistent with the expression trends of common inflammation-related genes IL1B and CD83.After virtual knockout of NUPR1,ATP metabolism and mitochondrial-related pathways were significantly perturbed(P＜0.05).Conclusion Colonic macrophages from UC patients exhibit a marked decline in OXPHOS function.NUPR1 is a key regulatory gene closely associated with this process,and its downregulation may impair macrophage OXPHOS capacity by affecting mitochondrial function and ATP metabolism.These findings provide a potential target and rationale interventions for regulating energy metabolism in UC.关键词
溃疡性结肠炎/巨噬细胞/氧化磷酸化/核蛋白转录因子1Key words
ulcerative colitis/macrophages/oxidative phosphorylation/nuclear protein 1,transcriptional regulator分类
医药卫生引用本文复制引用
余思睿,何佳利,巫明月,柴进..NUPR1下调介导巨噬细胞氧化磷酸化损伤参与溃疡性结肠炎发病[J].陆军军医大学学报,2026,48(11):1505-1517,13.基金项目
四大慢病重大专项(2026ZD0557000) （2026ZD0557000）
国家自然科学基金面上项目(82570651) （82570651）
重庆西南医院优青拔尖项目(2025YQBJ-5) （2025YQBJ-5）
重庆自然科学基金面上项目(CSTB2023NSCQ-MSQ0657) Supported by the Noncommunicable Chronic Diseases-National Science and Technology Major Project(2026ZD0557000),the General Program of National Natural Science Foundation of China(82570651),the Outstanding Young Scholar Project of Southwest Hospital(2025YQBJ-5),and the General Project of National Natural Science Foundation of Chongqing(CSTB2023NSCQ-MSQ0657). （CSTB2023NSCQ-MSQ0657）
