Page 74 - 南京医科大学自然版

南京医科大学学报（自然科学版） 第45卷第12期
·1756 · Journal of Nanjing Medical University（Natural Sciences） 2025年12月

·基础研究·

α⁃酮戊二酸通过XRCC3诱发急性胰腺炎发病的机制研究

侯超群，葛万里，彭云鹏，李 强 *
南京医科大学第一附属医院胰腺中心，江苏 南京 210029

［摘 要］ 目的：筛选急性胰腺炎（acute pancreatitis，AP）潜在致病代谢物，并基于动物及细胞模型探讨α ⁃酮戊二酸（alpha⁃
ketoglutarate，αKG）调控X线修复交叉互补3蛋白（X ray repair cross⁃complementing protein 3，XRCC3）诱发AP的分子机制。方
法：通过孟德尔随机化（Mendelian randomization，MR）研究，结合两轮独立的Meta分析，从遗传学角度筛选与AP发病相关的代
谢物，并采用逆方差加权（inverse variance weighted，IVW）方法评估代谢物与AP的因果效应。随后，构建C57BL/6小鼠AP动物
模型及AR42J细胞模型，分别通过腹腔注射αKG和培养基共培养的方式，验证其对胰腺腺泡细胞损伤及炎症反应的影响。检
测指标包括细胞活性、炎症因子水平、组织病理学变化。此外，利用RNA测序分析αKG处理前后AR42J细胞的全转录组差异，
并通过免疫组化、Western blot等技术验证XRCC3的表达变化及其在AP发病中的作用。结果：MR研究及Meta分析结果显示，
αKG与AP发病存在正向因果关系，而吲哚丙酸（indolepropionate，INDO）则表现出潜在的保护作用。细胞实验表明，10 μmol/L 的

αKG可显著抑制AR42J细胞活性，并促进白细胞介素（interleukin，IL）⁃6、IL⁃1β等炎症因子的分泌。动物模型中，腹腔注射αKG
可诱导小鼠AP的发生，表现为胰腺组织水肿、腺泡细胞损伤及血清炎症因子水平升高。全转录组测序结果表明αKG通过抑制
XRCC3的表达，削弱DNA损伤修复能力，从而加剧胰腺腺泡细胞损伤。免疫组化和Western blot 显示αKG处理后AR42J细胞
中XRCC3表达显著下调，此外，过表达XRCC3可在一定程度上逆转αKG对腺泡细胞的损伤作用。结论：本研究首次在遗传学
层面证实αKG是AP的致病代谢物，其通过抑制XRCC3介导的DNA修复通路，加剧胰腺腺泡细胞损伤及炎症反应。该发现为
AP的代谢机制研究提供了新视角，提示靶向αKG⁃XRCC3轴可能成为潜在治疗策略。
［关键词］ 急性胰腺炎；α⁃酮戊二酸；XRCC3；孟德尔随机化；DNA损伤修复
［中图分类号］ R576 ［文献标志码］ A ［文章编号］ 1007⁃4368（2025）12⁃1756⁃10
doi：10.7655/NYDXBNSN250807

Study on the mechanism of α⁃ketoglutarate inducing acute pancreatitis via XRCC3

HOU Chaoqun，GE Wanli，PENG Yunpeng，LI Qiang *
Pancreas Center，the First Affiliated Hospital of Nanjing Medical University，Nanjing 210029，China

［Abstract］ Objective：To screen potential pathogenic metabolites of acute pancreatitis（AP）and explore the molecular mechanism
of α⁃ketoglutarate（αKG）regulating X ray repair cross⁃complementing protein 3（XRCC3）to induce AP based on animal and cell
models. Methods：The study first conducted a Mendelian randomization（MR）study combined with two rounds of independent Meta⁃
analysis to screen metabolites related to the onset of AP from a genetic perspective，and used the inverse variance weighted（IVW）
method to evaluate the causal effect of metabolites on AP. Subsequently，AP animal models in C57BL/6 mice and AR42J cell models
were constructed. The effects of αKG on pancreatic acinar cell injury and inflammatory response were verified by intraperitoneal
injection of αKG and co⁃culture with the medium，respectively. The detection indicators included cell viability，levels of inflammatory
factors，and histopathological changes. In addition，RNA sequencing was used to analyze the whole transcriptome differences in AR42J
cells before and after αKG treatment，and the expression changes of XRCC3 and its role in the onset of AP were verified by
immunohistochemistry and Western blot techniques. Results：The MR study and Meta⁃analysis results showed that αKG had a positive
causal relationship with the onset of acute pancreatitis，while indolepropionate（INDO）showed a potential protective effect. Cell
experiments indicated that 10 μmol/L of αKG could significantly inhibit the viability of AR42J cells and promote the secretion of
inflammatory factors such as interleukin⁃6（IL⁃6）and IL⁃1β. In the animal model，intraperitoneal injection of αKG could induce the

［基金项目］ 江苏省科教能力提升工程（江苏省医学重点学科）（ZDXK202222）
通信作者（Corresponding author），E⁃mail：liqiang020202@163.com（ORCID：0000⁃0001⁃5129⁃2603）
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