目的：探讨苯扎氯铵(BAC)作为眼用制剂防腐剂导致干眼角膜损伤的毒性机制。

方法：采用网络毒理学方法，通过PubChem、CTD、ChEMBL、STITCH等数据库获取BAC的化学结构、毒性靶点及干眼相关角膜损伤靶点； 利用STRING数据库构建蛋白-蛋白相互作用网络，筛选关键毒性靶点； 通过GO功能注释和KEGG通路富集分析揭示BAC可能作用的生物学过程与信号通路； 进一步采用分子对接技术验证BAC与核心靶点(IL-6、IL-1β、TNF、EGF)的结合能力。

结果：BAC毒性等级为4级，具有显著眼部刺激性。共筛选出85个BAC与干眼角膜损伤的共同靶点，其中49个为关键毒性靶点，包括TNF、IL-6、TP53、IL-1β、BCL2等。KEGG富集分析显示BAC主要作用于IL-17、TNF、NF-κB、JAK-STAT、PI3K-Akt、Rap1和MAPK等7条与角膜损伤密切相关的信号通路。分子对接结果表明BAC与IL-6、IL-1β、TNF、EGF等靶点具有稳定的结合能力(结合能<0)。

结论：BAC可能通过多靶点、多通路机制诱导干眼角膜损伤，其作用涉及炎症反应、细胞凋亡、泪膜稳定性破坏及角膜修复延迟等过程，提示长期使用含BAC眼用制剂可能加重眼表损害。

METHODS:Network toxicology was employed to obtain the chemical structure of BAC, its toxic targets, and targets associated with dry eye-related corneal injury from databases including PubChem, CTD, ChEMBL, and STITCH. The protein-protein interaction(PPI)networks were constructed using the STRING database to screen key toxicity targets. Gene ontology(GO)functional annotation and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analyses were performed to elucidate the potential biological processes and signaling pathways affected by BAC. Furthermore, molecular docking techniques were employed to validate the binding affinity of BAC to its key targets(IL-6, IL-1β, TNF, and EGF).

RESULTS:BAC had a toxicity grade of 4 and exhibited significant eye irritation. A total of 85 common targets of BAC and dry eye corneal damage were screened out, of which 49 were key toxic targets, including TNF, IL-6, TP53, IL-1β, BCL2, etc. KEGG enrichment analysis showed that BAC mainly acted on 7 corneal injury pathways closely associated with corneal injury, such as IL-17, TNF, NF-κB, JAK-STAT, PI3K-Akt, Rap1, and MAPK. The results of molecular docking showed that BAC had stable binding ability to IL-6, IL-1β, TNF, EGF, and other targets(binding energy <0).

CONCLUSION:BAC may induce corneal damage in dry eye through multi-target and multi-pathway mechanisms, involving processes such as inflammatory response, apoptosis, disruption of tear film stability, and delayed corneal repair, which suggests that long-term use of ophthalmic preparations containing BAC may aggravate ocular surface damage.