目的：通过生物信息学和细胞实验研究ABCA4基因在干性ARMD中的作用机制。

方法：整合生物信息学与细胞实验，基于GEO数据集GSE29801筛选ARMD差异表达基因(DEGs)，通过PPI网络分析(STRING数据库)和拓扑参数筛选Hub基因。构建慢病毒介导的人视网膜色素上皮细胞(ARPE-19)ABCA4敲低稳转株(ABCA4-KD组)与阴性对照，使用NaIO₃建立氧化应激模型，分四组处理：NC组(阴性对照慢病毒+PBS)、NaIO₃+NC组(阴性对照慢病毒+氧化应激损伤)、ABCA4-KD组(ABCA4敲低慢病毒+PBS)、NaIO₃+ABCA4-KD组(ABCA4敲低慢病毒+氧化应激损伤)，通过Western blot验证敲低效率，CCK-8检测细胞活性，Hoechst 33342与Annexin V-FITC/PI双染色检测细胞凋亡率。

结果：生信分析筛选出5 069个DEGs(2 493个上调/2 576个下调)，与ARMD疾病靶点取交集获118个关键基因； PPI网络确定Top5 Hub基因(ABCA4、RPE65、PRPH2、RHO、PDE6B)，其中ABCA4度中心性最高(Degree=58)； ROC曲线显示ABCA4对ARMD鉴别效能极佳(AUC=0.986)。进一步细胞实验发现，ABCA4-KD组ABCA4蛋白表达显著低于NC组(P<0.05)； 在氧化应激条件下，NaIO₃+ABCA4-KD组细胞活性低于NaIO₃+NC组(P<0.01)，而细胞凋亡率显著升高(均P<0.01)，而在无氧化应激环境中，单纯敲低ABCA4未影响细胞存活(P>0.05)。

结论：ABCA4功能缺失通过加剧氧化应激诱导的RPE细胞凋亡参与ARMD病理进程，有望成为干性ARMD靶向治疗新靶点。

METHODS: Integrating bioinformatics and cellular experiments, differential expression genes(DEGs)associated with ARMD were screened based on the GEO dataset GSE29801. Hub genes were identified through PPI network analysis(using the STRING database)and topological parameter screening. A lentivirus-mediated stable ABCA4 knockdown cell line in human retinal pigment epithelial cells(ARPE-19; ABCA4-KD group)and a negative control were constructed. An oxidative stress model was established using NaIO₃, and the cells were divided into four treatment groups: NC group(negative control lentivirus+PBS), NaIO₃+NC group(negative control lentivirus+oxidative stress injury), ABCA4-KD group(ABCA4 knockdown lentivirus+PBS), NaIO₃+ABCA4-KD group(ABCA4 knockdown lentivirus+oxidative stress injury). Knockdown efficiency was verified via Western blot, cell viability was assessed using the CCK-8 assay, and the apoptosis rate was measured by Hoechst 33342 and Annexin V-FITC/PI double staining.

RESULTS: Bioinformatics analysis identified 5 069 DEGs(2 493 upregulated/2 576 downregulated), of which 118 key genes were obtained by intersecting with ARMD disease targets. PPI network analysis identified the top 5 hub genes(ABCA4, RPE65, PRPH2, RHO, PDE6B), with ABCA4 showing the highest degree centrality(Degree=58). ROC curve analysis demonstrated that ABCA4 had excellent discriminative efficacy for ARMD(AUC=0.986). Further cellular experiments revealed that ABCA4 protein expression in the ABCA4-KD group was significantly lower than that in the NC group(P<0.05). Under oxidative stress conditions, the NaIO₃+ABCA4-KD group exhibited lower cell viability compared to the NaIO₃+NC group(P<0.01), while the apoptosis rate was significantly increased(all P<0.01). In the absence of oxidative stress, knockdown of ABCA4 alone did not affect cell survival(P>0.05).

CONCLUSION: Loss of ABCA4 function contributes to the pathology of ARMD by exacerbating oxidative stress-induced RPE cell apoptosis, and is expected to serve as a novel therapeutic target for dry ARMD.