目的 探究11-羰基-β-乙酰乳香酸（acetyl-11-keto-β-boswellic acid，AKBA）对小鼠变应性接触性皮炎（allergic contact dermatitis，ACD）的治疗作用。方法 通过人工智能模型药物深度双线性注意力网络（drug deep bilinear attention network，DrugBAN）预测AKBA对ACD的治疗作用和潜在效应分子；利用方酸二丁酯建立小鼠ACD模型，评估AKBA的治疗效果，连续3 d给予AKBA治疗，记录小鼠挠痒次数、皮肤病变程度；通过苏木素-伊红染色和甲苯胺蓝染色观察小鼠颈部皮肤病理变化；应用转录组测序和分析，获取小鼠颈部皮肤差异表达基因；利用qRT-PCR和Western blotting检测AKBA对小鼠颈部皮肤组织中主要差异基因的表达水平及相关通路关键蛋白的调控作用。结果 DrugBAN预测AKBA可作用于肿瘤坏死因子受体1（tumor necrosis factor receptor 1，TNFR1），并干预Janus激酶-信号传导及转录激活因子（Janus kinase-signal transducer and activator of transcription，JAK-STAT）、趋化因子等信号通路治疗ACD。动物实验发现，AKBA显著降低ACD小鼠抓挠频率、改善颈部皮肤损伤（P＜0.05、0.01、0.001）；转录组学分析共得到169个共同差异基因，主要富集到丝裂原活化蛋白激酶（mitogen-activated protein kinase，MAPK）等信号通路。Western blotting验证结果显示AKBA能显著降低ACD小鼠颈部皮肤组织中TNFR1、磷酸化p38 MAPK、磷酸化细胞外信号调节激酶、磷酸化c-Jun氨基末端激酶和磷酸化STAT3蛋白的表达（P＜0.05、0.01、0.001）。qRT-PCR验证结果显示，AKBA显著下调ACD小鼠皮肤组织TNF-α、白细胞介素-1β（interleukin-1β，IL-1β）、IL-17、CXC基序趋化因子配体2（C-X-C motif chemokine ligand 2，CXCL2）、C-C基序趋化因子配体3（C-C motif chemokine ligand 3，CCL3）、CCL28的mRNA表达水平（P＜0.05、0.01、0.001）。结论 AKBA通过下调多种炎症因子表达，调控TNFR/MAPK和JAK-STAT信号通路发挥对ACD小鼠的治疗作用。

Objective To investigate the therapeutic effect of acetyl-11-keto-β-boswellic acid (AKBA) on allergic contact dermatitis (ACD) in mice. Methods Drug deep bilinear attention network (DrugBAN) artificial intelligence model was used to predict the characteristics of AKBA for ACD treatment. A mouse ACD model was established using squaric acid dibutylester to evaluate the effect of AKBA on ACD. AKBA was given on ACD mice for 3 d. The number of scratching times of mice was recorded, and the degree of skin lesions was evaluated. The pathological changes in mouse neck skin were observed by hematoxylin-eosin staining and toluidine blue staining. The differentially expressed genes in mouse neck skin were obtained by transcriptome sequencing and analysis. Furthermore, the expression levels of main differentially expressed genes and the regulation of key proteins of related pathways by AKBA were detected by qRT-PCR and Western blotting. Results DrugBAN analysis predicted that AKBA acted on effector molecules such as tumor necrosis factor receptor 1 (TNFR1) and interfered with Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway and chemokine signaling pathways to treat ACD. The animal experiments showed that AKBA could significantly reduce scratching bouts and improved neck skin damage in ACD mice (P < 0.05, 0.01 and 0.001). A total of 169 common differentially expressed genes were obtained from transcriptomics analysis, which were mainly enriched to mitogen-activated protein kinase (MAPK) signaling pathway. According to the results of Western blotting, AKBA significantly inhibited the expressions of TNFR1, phospho-p38 MAPK, phospho-extracellular regulated kinase 1/2, phospho-c-Jun N-terminal kinase and phospho-STAT3 in skin tissues of ACD mice (P < 0.05, 0.01, 0.001). The results of qRT-PCR also exhibited that AKBA significantly down-regulated the expression levels of TNF-α, interleukin-1β (IL-1β), IL-17, CXC chemokine ligand 2 (CXCL2), C-C motif chemokine ligand 3 (CCL3), and CCL28 in skin tissues of ACD mice (P < 0.05, 0.01, 0.001). Conclusion AKBA could exert a treatment effect in ACD mice by declining the expressions of various pro-inflammatory cytokines and modulating TNFR/MAPK and JAK-STAT signaling pathways.

R285.5

国家自然科学基金面上项目（82474188）；湖北省自然科学基金面上项目（2023AFB755）；重大疾病新药靶发现及新药创制全国重点实验室开放课题（SKLD2024M05）