目的 基于腺苷酸活化蛋白激酶（AMPK）/核因子红系 2 相关因子 2（NRF2）/溶质载体家族 7 成员 11 （SLC7A11）信号通路探讨香连丸对溃疡性结肠炎（UC）小鼠的作用及机制。方法 将 C57BL/6 小鼠随机分为正 常组、模型组、美沙拉嗪组（0.75 g·kg-1 ）及香连丸低、中、高剂量组（1.2、2.4、3.6 g·kg-1 ），每组 6 只。采用自 由饮用 3% 葡聚糖硫酸钠（DSS）溶液 7 d 诱导 UC 小鼠模型。造模第 1 天开始，各给药组均灌胃给予相应药物 （20 mL·kg-1 ），每日 1 次，连续 10 d。实验期间每日观察小鼠体质量变化、粪便黏稠度及隐血情况，进行疾病 活动指数（DAI）评分；采用 HE 及阿尔新蓝染色法检测结肠组织病理变化，并进行组织病理评分；ELISA 法检 测血清中 4-羟基壬烯醛（4-HNE）、髓过氧化物酶（MPO）、肿瘤坏死因子 α（TNF-α）、白细胞介素 1β（IL-1β） 水平；Western Blot 法检测结肠组织磷酸化腺苷酸活化蛋白激酶（P-AMPK）、AMPK、NRF2、SLC7A11、谷胱 甘肽过氧化物酶 4（GPX4）、前列腺素内过氧化物合酶 2（PTGS2）蛋白表达水平。结果 与正常组比较，模型组 小鼠的结肠长度显著缩短（P＜0.001），体质量显著降低（P＜0.001），DAI 评分显著增加（P＜0.001）；结肠组织 病理损伤明显，HE 染色可见黏膜层大量炎性细胞浸润，上皮结构被破坏，隐窝广泛缺失甚至形成溃疡，结肠 组织 HE 评分显著升高（P＜0.001）；阿尔新蓝染色显示杯状细胞数量急剧减少，蓝紫色黏液物质着色明显变 淡、稀疏，结肠组织阿尔新蓝评分显著降低（P＜0.001）；血清 4-HNE、MPO、IL-1β、TNF-α 水平均显著升高 （P＜0.01，P＜0.001）；结肠组织 NRF2、P-AMPK/AMPK、SLC7A11、GPX4 蛋白表达均显著下调（P＜0.01， P＜0.001），PTGS2 蛋白表达明显上调（P＜0.05）。与模型组比较，香连丸低、中、高剂量组小鼠的结肠长度明 显延长（P＜0.05，P＜0.01），香连丸高剂量组小鼠的体质量下降趋势明显变缓（P＜0.001），DAI 评分显著降低 （P＜0.001）；香连丸低、中、高剂量组及美沙拉嗪组小鼠结肠组织病理损伤得到明显改善，炎性细胞浸润程度 减轻，上皮结构及隐窝得到部分修复，结肠组织 HE 评分显著降低（P＜0.05，P＜0.01），杯状细胞数量及黏液 分泌得到有效恢复，结肠组织阿尔新蓝评分显著升高（P＜0.01，P＜0.001）；香连丸低、中、高剂量组小鼠的 血清 4-HNE、MPO、IL-1β、TNF-α 水平均显著降低（P＜0.05，P＜0.01，P＜0.001），结肠组织 NRF2、 P-AMPK/AMPK、SLC7A11、GPX4 蛋白表达均明显上调（P＜0.05，P＜0.01）；香连丸低、高剂量组的小鼠结肠 组织 PTGS2 蛋白表达明显下调（P＜0.05）。结论 香连丸能够明显改善 DSS 诱导的 UC 小鼠结肠组织病理损伤， 恢复肠屏障功能，具有抗炎、抗氧化应激作用，可能与激活 AMPK/NRF2/SLC7A11 信号通路抑制铁死亡有关。

Objective To investigate the effect and mechanism of Xianglian Pills on ulcerative colitis （UC） mice based on the adenosine monophosphate-activated protein kinase （AMPK）/nuclear factor erythroid 2-related factor 2（NRF2）/ solute carrier family 7 member 11（SLC7A11） signaling pathway. Methods C57BL/6 mice were randomly divided into a normal group，a model group，a mesalazine group （0.75 g·kg-1 ），and low-，medium-，and high-dose Xianglian Pills groups （1.2，2.4，3.6 g·kg-1 ），with 6 mice in each group. A UC mouse model was induced by allowing free access to 3% dextran sulfate sodium （DSS） solution for 7 days. Starting from the first day of modeling，each treatment group was orally administered the corresponding drug （20 mL·kg-1 ） once daily for 10 consecutive days. During the experiment，changes in body mass，fecal consistency，and occult blood were observed daily，and the disease activity index （DAI） was scored. Histopathological changes in colon tissue were detected by hematoxylin and eosin （HE） and Alcian blue staining， and histopathological scores were assessed. Serum levels of 4-hydroxynonenal （4-HNE）， myeloperoxidase （MPO），tumor necrosis factor-α（TNF-α），and interleukin-1β（IL-1β） were measured by ELISA. The protein expression levels of phosphorylated AMPK （P-AMPK）， AMPK， NRF2， SLC7A11， glutathione peroxidase 4（GPX4），and prostaglandin-endoperoxide synthase 2（PTGS2） in colon tissue were detected by Western Blot. Results Compared with the normal group， the model group showed significantly shortened colon length （P＜ 0.001）， significantly decreased body mass （P＜0.001）， and significantly increased DAI score （P＜0.001）. Colon tissue exhibited obvious pathological damage； HE staining revealed extensive inflammatory cell infiltration in the mucosal layer，disrupted epithelial structure，widespread crypt loss and even ulcer formation，and the HE score of colon tissue was significantly increased （P＜0.001）. Alcian blue staining showed a sharp decrease in the number of goblet cells，with markedly lighter and sparser blue-purple mucus staining，and the Alcian blue score of colon tissue was significantly decreased （P＜0.001）. Serum levels of 4-HNE，MPO，IL-1β，and TNF-α were all significantly elevated （P＜0.01，P＜0.001）. The protein expression of NRF2，P-AMPK/AMPK，SLC7A11，and GPX4 in colon tissue was significantly downregulated （P＜0.01， P＜0.001）， while PTGS2 protein expression was significantly upregulated （P＜0.05）. Compared with the model group，the low-，medium-，and high-dose Xianglian Pills groups showed significantly prolonged colon length （P＜0.05， P＜0.01）； the high-dose Xianglian Pills group exhibited a significantly slowed downward trend in body mass （P＜0.001） and a significantly decreased DAI score （P＜0.001）. Histopathological damage in colon tissue of the low- ， medium- ， and high-dose Xianglian Pills groups and the mesalazine group was significantly improved， with reduced inflammatory cell infiltration， partial repair of epithelial structure and crypts， and significantly decreased HE scores （P＜0.05， P＜0.01）. The number of goblet cells and mucus secretion were effectively restored，and the Alcian blue scores of colon tissue were significantly increased （P＜ 0.01， P＜0.001）. Serum levels of 4-HNE， MPO， IL-1β， and TNF- α in the low- ， medium- ， and high-dose Xianglian Pills groups were significantly decreased （P＜0.05，P＜0.01，P＜0.001）. The protein expression of NRF2， P-AMPK/AMPK，SLC7A11，and GPX4 in colon tissue was significantly upregulated （P＜0.05，P＜0.01）. PTGS2 protein expression was significantly downregulated in the low- and high-dose Xianglian Pills groups （P＜0.05）. Conclusion Xianglian Pills can significantly ameliorate colon tissue pathological damage， restore intestinal barrier function，and exert anti-inflammatory and anti-oxidative stress effects in DSS-induced UC mice. Its mechanism may be related to inhibiting ferroptosis by activating the AMPK/NRF2/SLC7A11 signaling pathway.

R285.5

国家自然科学基金青年项目（82404981）；梅州市医药卫生科研课题（2024-B-11）；梅州市人民医院（梅州市医学科学院）高层次 人才科研启动基金项目（KYQD202304，KYQD202305）。